Heterocytes as inhibitors of leucocyte adhesion and as VLA-4 antagonists

ABSTRACT

The present invention relates to compounds of the formula I 
                 
 
which are inhibitors of the adhesion and migration of leucocytes and/or antagonists of the adhesion receptor VLA-4 which belongs to the group of integrins. The invention also relates to processes for the preparation of formula I, pharmaceutical compositions containing compounds of formula I, and the treatment or prophylaxis of various diseases caused by or are associated with excess leucocyte adhesion and/or leucocyte migration, as well as diseases associated with cell-cell or cell-matrix interactions, which on interactions of VLA-4 receptors with their ligands play a part of, for example, inflammatory processes, rheumatoid arthritis or allergic disorders.

This application is a continuation of U.S. Ser. No. 08/971,966 filedNov. 17, 1997 now abandoned. The prior application is herebyincorporated herein by reference, in its entirety.

The present invention relates to compounds of the formula I

which are inhibitors of the adhesion and migration of leucocytes and/orantagonists of the adhesion receptor VLA-4 which belongs to the group ofintegrins. The invention also relates to processes for theirpreparation, to the use of compounds of the formula I for the treatmentor prophylaxis of diseases which are caused by an undesired extent ofleucocyte adhesion and/or leucocyte migration or which are associatedtherewith or in which cell-cell or cell-matrix interactions which arebased on interactions of VLA-4 receptors with their ligands play a part,for example of inflammatory processes, of rheumatoid arthritis or ofallergic disorders, and also to the use of compounds of the formula Ifor the production of pharmaceuticals for use in such diseases, and topharmaceutical preparations which contain the compounds of the formulaI.

The integrins are a group of adhesion receptors which play an importantpart in cell-cell-binding and cell-extracellular matrix-bindingprocesses. They have an αβ-heterodimeric structure and exhibit a widecellular distribution and a high extent of evolutive conservation. Theintegrins include, for example, the fibrinogen receptor on platelets,which interacts especially with the RGD sequence of fibrinogen, or thevitronectin receptor on osteoclasts, which interacts especially with theRGD sequence of vitronectin or of osteopontin. The integrins are dividedinto three major groups, the β2 subfamily with the representativesLFA-1, Mac-1 and p150/95, which are responsible in particular forcell-cell interactions of the immune system, and the subfamilies β1 andβ3, whose representatives mainly mediate cell adhesion to components ofthe extracellular matrix (Ruoslahti, Annu Rev. Biochem. 1988, 57, 375).The integrins of the β1 subfamily, also called VLA proteins (very late(activation) antigen), include at least six receptors which interactspecifically with fibronectin, collagen and/or laminin as ligands.Within the VLA family, the integrin VLA-4 (α4β1) is atypical in so faras it is mainly restricted to lymphoid and myeloid cells and isresponsible in these for cell-cell interactions with a large number ofother cells. For example, VLA-4 mediates the interaction of T and Blymphocytes with the heparin II-binding fragment of human plasmafibronectin (FN). The binding of VLA-4 with the heparin II-bindingfragment of plasma fibronectin is especially based on an interactionwith an (SEQ ID NO: 1) LDVP sequence. In contrast to the fibrinogen orvitronectin receptor, VLA-4 is not a typical RGD-binding integrin(Kilger and Holzmann, J. Mol. Meth. 1995, 73, 347).

The leucocytes circulating in the blood normally exhibit only a lowaffinity for the vascular endothelial cells which line the bloodvessels. Cytokines which are released from inflamed tissue cause theactivation of endothelial cells and thus the expression of a largenumber of cell surface antigens. These include, for example, theadhesion molecules ELAM-1 (endothelial cell adhesion molecule-1; alsodesignated as E-selectin), which, inter alia, binds neutrophils, ICAM-1(intercellular adhesion molecule-1), which interacts with LFA-1(leucocyte function-associated antigen 1) on leucocytes, and VCAM-1(vascular cell adhesion molecule-1), which binds various leucocytes,inter alia lymphocytes (Osborn et al., Cell 1989, 59, 1203). VCAM-1,like ICAM-1, is a member of the immunoglobulin gene superfamily. VCAM-1(first known as INCAM-110) was identified as an adhesion molecule whichis induced on endothelial cells by inflammatory cytokines such as TNFand IL-1 and lipopolysaccharides (LPS). Elices et al. (Cell 1990, 60,577) showed that VLA-4 and VCAM-1 form a receptor-ligand pair whichmediates the adhesion of lymphocytes to activated endothelium. Thebinding of VCAM-1 to VLA-4 does not take place here due to aninteraction of the VLA-4 with an RGD sequence; such one is not containedin VCAM-1 (Bergelson et al., Current Biology 1995, 5, 615). VLA-4,however, also occurs on other leucocytes, and the adhesion of leucocytesother than lymphocytes is also mediated via the VCAM-1/VLA-4 adhesionmechanism. VLA-4 thus represents an individual example of a β1 integrinreceptor which, via the ligands VCAM-1 and fibronectin, plays animportant part in cell-cell interactions and in cell-extracellularmatrix interactions.

The cytokine-induced adhesion molecules play an important part in therecruitment of leucocytes into extravascular tissue regions. Leucocytesare recruited into inflammatory tissue regions by cell adhesionmolecules which are expressed on the surface of endothelial cells andserve as ligands for leucocyte cell surface proteins or proteincomplexes (receptors) (the terms ligand and receptor can also be usedvice versa). Leucocytes from the blood must first adhere to endothelialcells before they can migrate into the synovium. Since VCAM-1 binds tocells which carry the integrin VLA-4 (α4β1), such as eosinophils, T andB lymphocytes, monocytes or also neutrophils, it and the VCAM-1/VLA-4mechanism have the function of recruiting cells of this type from theblood stream into areas of infection and inflammatory foci (Elices etal., Cell 1990, 60, 577; Osborn, Cell 1990, 62, 3; Issekutz et al., J.Exp. Med. 1996, 183, 2175).

The VCAM-1/VLA-4 adhesion mechanism has been connected with a number ofphysiological and pathological processes. Apart from cytokine-inducedendothelium, VCAM-1 is additionally expressed, inter alia, by thefollowing cells: myoblasts, lymphoid dendritic cells and tissuemacrophages, rheumatoid synovium, cytokine-stimulated neural cells,parietal epithelial cells of the Bowman's capsule, the renal tubularepithelium, inflamed tissue during heart and kidney transplant rejectionand by intestinal tissue in graft-versus-host disease. VCAM-1 is alsofound to be expressed on those tissue areas of the arterial endotheliumwhich correspond to early arteriosclerotic plaques of a rabbit model.Additionally, VCAM-1 is expressed on follicular dendritic cells of humanlymph nodes and is found on stroma cells of the bone marrow, for examplein the mouse. The latter finding points to a function of VCAM-1 inB-cell development. Apart from cells of hematopoietic origin, VLA-4 isalso found, for example, on melanoma cell lines, and the VCAM-1/VLA-4adhesion mechanism is connected with the metastasis of such tumors (Riceet al., Science 1989, 246, 1303).

The main form in which VCAM-1 occurs in vivo on endothelial cells andwhich is the dominant form in vivo is designated as VCAM-7D and carriesseven immunoglobulin domains. The domains 4, 5 and 6 are similar intheir amino acid sequences to the domains 1, 2 and 3. The fourth domainis removed in a further form, consisting of six domains, designated hereas VCAM-6D, by alternative splicing. VCAM-6D can also bind VLA-4-expressing cells.

Further details on VLA-4, VCAM-1, integrins and adhesion proteins arefound, for example, in the articles by Kilger and Holzmann, J. Mol.Meth. 1995, 73, 347; Elices, Cell Adhesion in Human Disease, Wiley,Chichester 1995, p. 79; Kuijpers, Springer Semin. Immunopathol. 1995,16, 379.

On account of the role of the VCAM-1/VLA-4 mechanism in cell adhesionprocesses which are of importance, for example, in infections,inflammations or atherosclerosis, it has been attempted by means ofinterventions into these adhesion processes to control diseases, inparticular, for example, inflammations (Osborn et al., Cell 1989, 59,1203). A method of doing this is the use of monoclonal antibodies whichare directed against VLA-4. Monoclonal antibodies (mAB) of this typewhich as VLA-4 antagonists block the interaction between VCAM-1 andVLA-4, are known. Thus, for example, the anti-VLA-4 mAB HP2/1 and HP1/3inhibit the adhesion of VLA-4-expressing Ramos cells (B-cell-like cells)to human umbilical cord endothelial cells and to VCAM-1-transfected COScells.

The anti-VCAM-1 mAB 4B9 likewise inhibits the adhesion of Ramos cells,Jurkat cells (T-cell-like cells) and HL60 cells (granulocyte-like cells)to COS cells transfected with genetic constructs which cause VCAM-6D andVCAM-7D to be expressed. In vitro data with antibodies which aredirected against the α4 subunit of VLA-4 show that the adhesion oflymphocytes to synovial endothelial cells is blocked, an adhesion whichplays a part in rheumatoid arthritis (van Dinther-Janssen et al., J.Immunol. 1991, 147, 4207).

In vivo experiments have shown that an experimental autoimmuneencephalomyelitis can be inhibited by anti-α4 mAB. The migration ofleucocytes into an inflammatory focus is likewise blocked by amonoclonal antibody against the α4 chain of VLA-4. The influencing ofthe VLA-4-dependent adhesion mechanism by antibodies was alsoinvestigated in an asthma model in order to investigate the role ofVLA-4 in the recruitment of leucocytes in inflamed lung tissue (U.S.Ser. No. 07/821,768 now abandoned; EP-A-626 861). The administration ofanti-VLA-4 antibodies inhibited the late-phase reaction and respiratorytract overreaction in allergic sheep.

The VLA-4-dependent cell adhesion mechanism was also investigated in aprimate model of inflammatory bowel disease (IBD). In this model, whichcorresponds to ulcerative colitis in man, the administration ofanti-VLA-4 antibodies resulted in a significant reduction in the acuteinflammation.

Moreover, it was possible to show that VLA-4-dependent cell adhesionplays apart in the following clinical conditions including the followingchronic inflammatory processes: rheumatoid arthritis (Cronstein andWeismann, Arthritis Rheum. 1993, 36, 147; Elices et al., J. Clin.Invest. 1994, 93, 405), diabetes mellitus (Yang et al., Proc. Natl.Acad. Sci. USA 1993, 90, 10494), systemic lupus erythematosus (Takeuchiet al., J. Clin. Invest. 1993, 92, 3008), allergies of the delayed type(type IV allergy) (Elices et al., Clin. Exp. Rheumatol. 1993, 11, p.77),multiple sclerosis (Yednock et al., Nature 1992, 356, 63), malaria(Ockenhouse et al., J. Exp. Med. 1992, 176, 1183), arteriosclerosis(Obrien et al., J. Clin. Invest. 1993, 92, 945), transplantation (Isobeet al., Transplantation Proceedings 1994, 26, 867-868), variousmalignancies, for example melanoma (Renkonen et al., Am. J. Pathol.1992, 140, 763), lymphoma (Freedman et al., Blood 1992, 79, 206) andothers (Albelda et al., J. Cell Biol. 1991, 114, 1059).

VLA-4 blocking by suitable antagonists accordingly offers effectivetherapeutic possibilities, in particular, for example, of treatingvarious inflammatory conditions including asthma and IBD. The particularrelevance of VLA-4 antagonists for the treatment of rheumatoid arthritisin this respect results, as already stated, from the fact thatleucocytes from the blood must first adhere to endothelial cells beforethey can migrate into the synovium, and that the VLA-4 receptor plays apart in this adhesion. The fact that VCAM-1 is induced by inflammatoryagents on endothelial cells (Osborn, Cell 1990, 62, 3; Stoolman, Cell1989, 56, 907), and the recruitment of various leucocytes into areas ofinfection and inflammatory foci has already been dealt with above. Inthis respect, T cells adhere to activated endothelium mainly via theLFA-1/ICAM-1and VLA-4/VCAM-1 adhesion mechanisms (Springer, Cell 1994,76, 301). On most synovial T cells, the binding capacity of VLA-4 forVCAM-1 is increased in rheumatoid arthritis (Postigo et al., J. Clin.Invest. 1992, 89, 1445). Additionally, an increased adhesion of synovialT cells to fibronectin has been observed (Laffon et al., J. Clin.Invest. 1991, 88, 546; Morales-Ducret et al., J. Immunol. 1992, 149,1424). VLA-4 is also upregulated both in the course of its expressionand with respect to its function on T lymphocytes of the rheumatoidsynovial membrane. The blocking of the binding of VLA-4 to itsphysiological ligands VCAM-1 and fibronectin makes possible an effectiveprevention or alleviation of articular inflammatory processes. This isalso confirmed by experiments with the antibody HP2/1 on Lewis rats withadjuvant arthritis, in which an effective prevention of illness has beenobserved (Barbadillo et al., Springer Semin. Immunopathol. 1995, 16,427). VLA-4 is thus an important therapeutic target molecule.

The abovementioned VLA-4 antibodies and the use of antibodies as VLA-4antagonists are described in the Patent Applications WO-A-93/13798,WO-A-93/15764, WO-A-94/16094, WO-A-94/17828 and WO-A-95/19790. In thePatent Applications WO-A-94/15958, WO-A-95/15973, WO-A-96/00581,WO-A-96/06108 and WO-A-96/20216, peptide compounds are described asVLA-4 antagonists. The use of antibodies and peptide compounds aspharmaceuticals, however, is afflicted with disadvantages, for examplelack of oral availability, easy degradability or immunogenic action onlonger-term use, and there is thus a need for VLA-4 antagonists having afavorable profile of properties for use in therapy and prophylaxis.

WO-A-95/14008 describes substituted 5-membered ring heterocycles whichhave an amino, amidino or guanidino function at the N-terminal end ofthe molecule and which exhibit platelet aggregation-inhibiting activity.The German Patent Application 19635522.2 describes heterocycles whichare inhibitors of bone resorption. WO-A-96/33976 (and the German PatentApplication 19515177.1) describes certain hydantoin derivatives having a4-cyanophenyl radical in the 4-position of the hydantoin ring, which areintermediates for the preparation of active compounds which aredescribed in WO-A-95/14008. Pharmacological actions of thesecyanophenylhydantoin derivatives, however, are not disclosed. Thepresent invention relates to further heterocyclic compounds which areVLA-4 antagonists and/or inhibitors of leucocyte adhesion.

The present invention relates to compounds of the formula I

in which

-   W is R¹—A—C(R¹³) or R¹—A—CH═C;-   Y is a carbonyl, thiocarbonyl or methylene group;-   Z is N(R⁰), oxygen, sulfur or a methylene group;-   A is a bivalent radical selected from the group consisting of    (C₁-C₆)-alkylene, (C₃-C₁₂)-cycloalkylene,    (C₁-C₆)-alkylene-(C₃-C₁₂)-cycloalkyl, phenylene,    phenylene-(C₁-C₆)-alkyl, (C₁-C₆)-alkylenephenyl,    (C₁-C₆)-alkylenephenyl-(C₁-C₆)-alkyl, phenylene-(C₂-C₆)-alkenyl or a    bivalent radical of a 5- or 6-membered saturated or unsaturated ring    which can contain 1 or 2 nitrogen atoms and can be mono- or    disubstituted by (C₁-C₆)-alkyl or doubly bonded oxygen or sulfur, or    is a direct bond;-   B is a bivalent radical from the group consisting of    (C₁-C₆)-alkylene, (C₂-C₆)-alkenylene, phenylene,    phenylene-(C₁-C₃)-alkyl, and (C₁-C₃)-alkylenephenyl, where the    bivalent (C₁-C₆)-alkylene radical can be unsubstituted or    substituted by a radical from the group consisting of (C₁-C₈)-alkyl,    (C₂-C₈)-alkenyl, (C₂-C₈)-alkynyl, (C₃-C₁₀)-cycloalkyl,    (C₃-C₁₀)-cycloalkyl-(C₁-C₆)-alkyl, optionally substituted    (C₆-C₁₄)-aryl, (C₆-C₁₄)-aryl-(C₁-C₆)-alkyl optionally substituted in    the aryl radical, optionally substituted heteroaryl and    heteroaryl-(C₁-C₆)-alkyl optionally substituted in the heteroaryl    radical;-   D is C(R²)(R³), N(R³) or CH═C(R³);-   E is tetrazolyl, (R⁸O)₂P(O), HOS(O)₂, R⁹NHS(O)₂ or R¹⁰CO;-   R is hydrogen, (C₁-C₈)-alkyl, (C₃-C₁₂)-cycloalkyl,    (C₃-C₁₂)-cycloalkyl-(C₁-C₈)-alkyl, optionally substituted    (C₆-C₁₄)-aryl, (C₆-C₁₄)-aryl-(C₁-C₈)-alkyl optionally substituted in    the aryl radical, optionally substituted heteroaryl or    heteroaryl-(C₁-C₈)-alkyl optionally substituted in the heteroaryl    radical, where alkyl radicals can be mono- or polysubstituted by    fluorine;-   R⁰ is hydrogen, (C₁-C₈)-alkyl, (C₃-C₁₂)-cycloalkyl,    (C₃-C₁₂)-cycloalkyl-(C₁-C₈)-alkyl, (C₆-C₁₂)-bicycloalkyl,    (C₆-C₁₂)-bicycloalkyl-(C₁-C₈)-alkyl, (C₆-C₁₂)-tricycloalkyl,    (C₆-C₁₂)-tricycloalkyl-(C₁-C₈)-alkyl, optionally substituted    (C₆-C₁₄)-aryl, (C₆-C₁₄)-aryl-(C₁-C₈)-alkyl optionally substituted in    the aryl radical, optionally substituted heteroaryl,    heteroaryl-(C₁-C₈)-alkyl optionally substituted in the heteroaryl    radical, CHO, (C₁-C₈)-alkyl-CO, (C₃-C₁₂)-cycloalkyl-CO,    (C₃-C₁₂)-cycloalkyl-(C₁-C₈)-alkyl-CO, (C₆-C₁₂)-bicycloalkyl-CO,    (C₆-C₁₂)-bicycloalkyl-(C₁-C₈)-alkyl-CO, (C₆-C₁₂)-tricycloalkyl-CO,    (C₆-C₁₂)-tricycloalkyl-(C₁-C₈)-alkyl-CO, optionally substituted    (C₆-C₁₄)-aryl-CO, (C₆-C₁₄)-aryl-(C₁-C₈)-alkyl-CO optionally    substituted in the aryl radical, optionally substituted    heteroaryl-CO, heteroaryl-(C₁-C₈)-alkyl-CO optionally substituted in    the heteroaryl radical, (C₁-C₈)-alkyl-S(O)_(n),    (C₃-C₁₂)-cycloalkyl-S(O)_(n),    (C₃-C₁₂)-cycloalkyl-(C₁-C₈)-alkyl-S(O)_(n),    (C₆-C₁₂)-bicycloalkyl-S(O)_(n),    (C₆-C₁₂)-bicycloalkyl-(C₁-C₈)-alkyl-S(O)_(n),    (C₆-C₁₂)-tricycloalkyl-S(O)_(n),    (C₆-C₁₂)-tricycloalkyl-(C₁-C₈)-alkyl-S(O)_(n), optionally    substituted (C₆-C₁₄)-aryl-S(O)_(n),    (C₆-C₁₄)-aryl-(C₁-C₈)-alkyl-S(O)_(n) optionally substituted in the    aryl radical, optionally substituted heteroaryl-S(O)_(n) or    heteroaryl-(C₁-C₈)-alkyl-S(O)_(n) optionally substituted in the    heteroaryl radical, where n is 1 or 2;-   R¹ is one of the radicals —S—R²¹, —S—S—R²¹, —S(O)—R²², —S(O)₂—R²²,    —S—OR²¹, —S(O)—OR²¹, —S(O)₂—OR²¹, —S—N(R²¹)—R²⁸, —S(O)—N(R²¹)—R²⁸,    —S(O)₂—N(R²¹)—R²⁸, —S—C(O)—R²¹, —S—C(O)—OR²², —S—C(S)—SR²²,    —S—C(O)—N(R²¹)—R²⁸, —S—C(S)—N(R²¹)—R²⁸, —O—C(O)—R²¹, —O—C(S)—R²¹,    —O—C(O)—OR²², —O—C(O)—N(R²¹)—R²⁸, —O—C(S)—N(R²¹)—R²⁸, —O—S(O)₂—OR²¹,    —O—S(O)—OR²¹, —O—S(O)₂—N(R²¹)—R²⁸, —O—S(O)—N(R²¹)—R²⁸, —O—S(O)₂—R²²,    —O—S(O)—R²², —O—P(O)(OR²¹)₂, —O—P(O)(OR²¹)—N(R²¹)—R²⁸,    —O—P(O)(N(R²¹)—R²⁸)₂, —N(R²⁹)—C(O)—OR²², —N(R²⁸)—C(O)—SR²²,    —N(R²⁸)—C(S)—OR²², —N(R²⁸)—C(S)—SR²², —N(R²⁸)—C(S)—R²¹,    —N(R²⁸)—C(O)—N(R²¹)—R²⁸, —N(R²⁸)—C(S)—N(R²¹)—R²⁸, —N(R²⁸)—S(O)₂—R²²,    —N(R²⁸)—S(O)—R²², —N(R²⁸)—S(O)₂—OR²¹, —N(R²⁸)—S(O)—OR²¹,    —N(R²⁸)—S(O)₂—N(R²¹)—R²⁸, —N(R²⁸)—S(O)—N(R²¹)—R²⁸,    —N(R²⁸)—P(O)(OR²¹)₂, —N(R²⁸)—P(O)(OR²¹)—N(R²¹)—R²⁸,    —N(R²⁸)—P(O)(N(R²¹)—R²⁸)₂, —N(R²⁸)—P(O)(R²²)—OR²¹,    —N(R²⁸)—P(O)(R²²)—N(R²¹)R²⁸, —N(R²⁸)—P(O)(R²²)₂, —P(O)(OR²¹)₂,    —P(O)(OR²¹)—N(R²¹)—R²⁸, —P(O)(N(R²¹)—R²⁸)₂, —P(O)(R²²)—OR²¹,    —P(O)(R²²)—N(R²¹)—R²⁸, —P(O)(R²²)₂, —C(S)—R²¹, —C(S)—SR²¹,    —C(S)—N(R²¹)—R²⁸, cyano, halogen, nitro or methylenedioxy or the    radical of an optionally substituted, 5- to 14-membered, mono- or    polycyclic, saturated or unsaturated heterocyclic ring of the    formula-    in which    -   Q¹ is —C(R²¹)₂—, ═C(R²¹)—, —N(R²⁸)—, —O— or —S—;    -   Q² is —S(O)— or —S(O)₂—;    -   Q³ is —C(R²¹)₂—, ═C(R²¹)—, —N(R²⁸)—, —O—, —S—, —C(R²¹)(—)— or        —N(—)—,-    where the heterocyclic ring can be bonded to the group A via the    free bond in the groups —C(R²¹)(—)— or —N(—)— representing Q³ or via    any other desired ring carbon atom and where, if the heterocyclic    ring is bonded to a ring system contained in the group A, the    heterocyclic ring can also be fused via two adjacent atoms to the    ring system in the group A;-   R² is hydrogen, (C₁-C₈)-alkyl, optionally substituted (C₆-C₁₄)-aryl,    (C₆-C₁₄)-aryl-(C₁-C₁ alkyl-alkyl optionally substituted in the aryl    radical or (C₃-C₈)-cycloalkyl;-   R³ is hydrogen, (C₁-C₈) alkyl, optionally substituted (C₆-C₁₄)-aryl,    (C₆-C₁₄)-aryl-(C₁-C₈)-alkyl optionally substituted in the aryl    radical, (C₃-C₈)-cycloalkyl, (C₂-C₈)-alkenyl, (C₂-C₈)-alkynyl,    (C₂-C₈)-alkenylcarbonyl, (C₂-C₈)-alkynylcarbonyl, pyridyl, R¹¹NH,    R⁴CO, COOR⁴, CON(CH₃)R⁴, CONHR⁴, CSNHR⁴, COOR¹⁵, CON(CH₃)R¹⁵ or    CONHR¹⁵;-   R⁴ is hydrogen or (C₁-C₂₈)-alkyl which can optionally be mono- or    polysubstituted by identical or different radicals from the group    consisting of hydroxyl, hydroxycarbonyl, aminocarbonyl, mono- or    di-((C₁-C₁₈)-alkyl)-aminocarbonyl,    amino-(C₂-C₁₈)-alkylaminocarbonyl,    amino-(C₁-C₃)-alkylphenyl-(C₁-C₃)-alkylaminocarbonyl,    (C₁-C₁₈)-alkylcarbonylamino-(C₁-C₃)-alkylphenyl-(C₁-C₃)-alkylaminocarbonyl,    (C₁-C₁₈)-alkylcarbonylamino-(C₂-C₁₈)-alkylaminocarbonyl,    (C₆-C₁₄)-aryl-(C₁-C₈)-alkoxycarbonyl which can also be substituted    in the aryl radical, amino, mercapto, (C₁-C₁₈)-alkoxy,    (C₁-C₁₈)-alkoxycarbonyl, Het-CO, optionally substituted    (C₃-C₈)-cycloalkyl, HOS(O)₂-(C₁-C₃)-alkyl, R⁹NHS(O)₂—(C₁-C₃)-alkyl,    (R⁸O)₂P(O)—(C₁-C₃)-alkyl, tetrazolyl-(C₁-C₃)-alkyl, halogen, nitro,    trifluoromethyl or the radical R⁵;-   R⁵ is optionally substituted (C₆-C₁₄)-aryl,    (C₆-C₁₄)-aryl-(C₁-C₈)-alkyl optionally substituted in the aryl    radical, a mono- or bicyclic 5- to 12-membered heterocyclic ring    which can be aromatic, partially hydrogenated or completely    hydrogenated and which can contain one, two or three identical or    different heteroatoms from the group consisting of nitrogen, oxygen    and sulfur, a radical R⁶ or a radical R⁶CO—, where the aryl radical    and, independently thereof, the heterocyclic radical can be mono- or    polysubstituted by identical or different radicals from the group    consisting of (C₁-C₁₈)-alkyl, (C₁-C₁₈)-alkoxy, halogen, nitro, amino    and trifluoromethyl;-   R⁶ is R⁷R⁸N, R⁷O or R⁷S or an amino acid side chain, a natural or    unnatural amino acid, imino acid, optionally N—(C₁-C₈)-alkylated or    N—((C₆-C₁₄)-aryl-(C₁-C₈)-alkylated) azaamino acid or a dipeptide    radical which can also be substituted in the aryl radical and/or    reduced in the peptide bond to —NH—CH₂—, and their esters and    amides, where hydrogen or hydroxymethyl can optionally stand in    place of of free functional groups and/or where free functional    groups can be protected by protective groups customary in peptide    chemistry;-   R⁷ is hydrogen, (C₁-C₁₈)-alkyl, (C₆-C₁₄)-aryl-(C₁-C₈)-alkyl,    (C₁-C₁₈)-alkylcarbonyl, (C₁-C₁₈)-alkoxycarbonyl,    (C₆-C₁₄)-arylcarbonyl, (C₆-C₁₄)-aryl-(C₁-C₈)-alkylcarbonyl or    (C₆-C₁₄)-aryl-(C₁-C₁₈)-alkyloxycarbonyl, where the alkyl groups can    optionally be substituted by an amino group and/or where the aryl    radicals can be mono- or polysubstituted, preferably    monosubstituted, by identical or different radicals from the group    consisting of (C₁-C₈)-alkyl, (C₁-C₈)-alkoxy, halogen, nitro, amino    and trifluoromethyl, or R⁷ is a natural or unnatural amino acid,    imino acid, optionally N—(C₁-C₈)-alkylated or    N—((C₆-C₁₄)-aryl-(C₁-C₈)-alkylated) azaamino acid or a dipeptide    radical which can also be substituted in the aryl radical and/or    reduced in the peptide bond to —NH—CH₂—;-   R⁸ is hydrogen, (C₁-C₁₈)-alkyl, optionally substituted (C₆-C₁₄)-aryl    or (C₆-C₁₄)-aryl-(C₁-C₈)-alkyl which can also be substituted in the    aryl radical;-   R⁹ is hydrogen, aminocarbonyl, (C₁-C₁₈)-alkylaminocarbonyl,    (C₃-C₈)-cycloalkylaminocarbonyl, optionally substituted    (C₆-C₁₄)-arylaminocarbonyl, (C₁-C₁₈)-alkyl, optionally substituted    (C₆-C₁₄)-aryl or (C₃-C₈)-cycloalkyl;-   R¹⁰ is hydroxyl, (C₁-C₁₈)-alkoxy, (C₆-C₁₄)-aryl-(C₁-C₈)-alkoxy which    can also be substituted in the aryl radical, optionally substituted    (C₆-C₁₄)-aryloxy, amino or mono- or di-((C₁-C₁₈)-alkyl)amino;-   R¹¹ is hydrogen, R^(12a), R^(12a)—CO, H—CO, R^(12a)—O—CO,    R^(12b)—CO, R^(12b)—CS, R^(12a)—S(O)₂ or R^(12b)—S(O)₂;-   R^(12a) is (C₁-C₁₈)-alkyl, (C₂-C₈)-alkenyl, (C₂-C₈)-alkynyl,    (C₃-C₁₂-Cycloalkyl, (C₃-C₁₂)-cycloalkyl-(C₁-C₈)-alkyl, optionally    substituted (C₆-C₁₄)-aryl, (C₆-C₁₄)-aryl-(C₁-C₈)-alkyl optionally    substituted in the aryl radical, optionally substituted heteroaryl,    heteroaryl-(C₁-C₈)-alkyl optionally substituted in the heteroaryl    radical or the radical R¹⁵;-   R^(12b) is amino, di-((C₁-C₁₈)-alkyl)-amino or R^(12a)—NH;-   R¹³ is hydrogen, (C₁-C₆)-alkyl, optionally substituted    (C₆-C₁₄)-aryl, (C₆-C₁₄)-aryl-(C₁-C₈)-alkyl optionally substituted in    the aryl radical, (C₃-C₈)-cycloalkyl or    (C₃-C₈)-cycloalkyl-(C₁-C₈)-alkyl;-   R¹⁵ is R¹⁶—(C₁-C₆)-alkyl or R¹⁶;-   R¹⁶ is a 6- to 24-membered bicyclic or tricyclic radical which is    saturated or partially unsaturated and which can also contain one,    two, three or four identical or different heteroatoms from the group    consisting of nitrogen, oxygen and sulfur and which can also be    substituted by one or more identical or different substituents from    the group consisting of (C₁-C₄)-alkyl and oxo;-   R²¹ is hydrogen, (C₁-C₈)-alkyl, hydroxy-(C₁-C₈)-alkyl,    (C₂-C₈)-alkenyl, (C₃-C₁₂)-cycloalkyl,    (C₃-C₁₂)-cycloalkyl-(C₁-C₈)-alkyl, optionally substituted    (C₆-C₁₄)-aryl, (C₆-C₁₄)-aryl-(C₁-C₈)-alkyl optionally substituted in    the aryl radical, optionally substituted heteroaryl or    heteroaryl-(C₁-C₈)-alkyl optionally substituted in the heteroaryl    radical, where alkyl radicals can also be monosubstituted or    polysubstituted by fluorine and the radicals R²¹ can be identical or    different if they occur two or more times;-   R²² is (C₁-C₈)-alkyl, hydroxy-(C₁-C₈)-alkyl, (C₂-C₈)-alkenyl,    (C₃-C₁₂)-cycloalkyl, (C₃-C₁₂)-cycloalkyl-(C₁-C₈)-alkyl, optionally    substituted (C₆-C₁₄)-aryl, (C₆-C₁₄)-aryl-(C₁-C₈)-alkyl optionally    substituted in the aryl radical, optionally substituted heteroaryl    or heteroaryl-(C₁-C₈)-alkyl optionally substituted in the heteroaryl    radical, where alkyl radicals can be monosubstituted or    polysubstituted by fluorine and the radicals R²² can be identical or    different if they occur two or more times;-   R²⁸ is one of the radicals R²¹—, R²¹N(R²¹)—, R²¹C(O)—, R²²O—C(O)—,    R²¹N(R²¹)—C(O)— or R²¹N(R²¹)—C(═N(R²¹))—;-   R²⁹ is one of the radicals R²²—, R²¹N(R²¹)—, R²¹C(O)—, R²²O—C(O)—,    R²¹N(R²¹)—C(O)— or R²¹N(R²¹)—C(═N(R²¹))—;-   Het is the radical of a 5- to 10-membered, monocyclic or polycyclic    heterocycle bonded via a nitrogen atom, which can be aromatic or    partially unsaturated or saturated and which can contain one, two,    three or four identical or different additional ring heteroatoms    from the group consisting of oxygen, nitrogen and sulfur and which    can be optionally substituted on carbon atoms and on additional ring    nitrogen atoms, where there can be identical or different radicals    R^(h), R^(h)CO or R^(h)O—CO as substituents on additional ring    nitrogen atoms and R^(h) is hydrogen, (C₁-C₈)-alkyl,    (C₃-C₈)-cycloalkyl, (C₃-C₈)-cycloalkyl-(C₁-C₈)-alkyl, optionally    substituted (C₆-C₁₄)-aryl or (C₆-C₁₄)-aryl-(C₁-C₈)-alkyl optionally    substituted in the aryl radical;

b, c, d and f independently of one another are 0 or 1, but cannot allsimultaneously be 0;

e, g and h independently of one another are 0, 1, 2, 3, 4, 5 or 6;

in all their stereoisomeric forms and mixtures thereof in any ratio, andtheir physiologically tolerable salts;

where, however, if simultaneously W is 4-cyanophenyl-C(R¹³), Y is acarbonyl group, Z is NR^(0a), B is an unsubstituted methylene group, Ris R^(a), b, c and d are 1 and e, f and g are 0, then D cannot beC(R^(2a))(R^(3a)), where

-   R^(0a), R^(a) and R^(2a) independently of one another are hydrogen,    (C₁-C₈)-alkyl, optionally substituted (C₆-C₁₄)-aryl,    (C₆-C₁₄)-aryl-(C₁-C₈)-alkyl optionally substituted in the aryl    radical or (C₃-C₈)-cycloalkyl and-   R^(3a) is hydrogen, (C₁-C₈)-alkyl, optionally substituted    (C₆-C₁₄)-aryl, (C₆-C₁₄)-aryl-(C₁-C₈)-alkyl optionally substituted in    the aryl radical, (C₃-C₈)-cycloalkyl or 2-, 3- or 4-pyridyl.

Alkyl radicals can be straight-chain or branched. This also applies ifthey carry substituents or occur as substituents of other radicals, forexample in alkoxy, alkoxycarbonyl or aralkyl radicals. The same appliesto alkylene radicals. Examples of suitable (C₁-C₂₈)-alkyl radicals are:methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, decyl,undecyl, dodecyl, tridecyl, pentadecyl, hexadecyl, heptadecyl,nonadecyl, eicosyl, docosyl, tricosyl, pentacosyl, hexacosyl,heptacosyl, octacosyl, isopropyl, isobutyl, isopentyl, neopentyl,isohexyl, 3-methylpentyl, 2,3,5-trimethylhexyl, sec-butyl, tert-butyl,tert-pentyl. Preferred alkyl radicals are methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl and tert-butyl. Examples ofalkylene radicals are methylene, ethylene, tri-, tetra-, penta- andhexamethylene or methylene substituted by an alkyl radical, for examplemethylene which is substituted by a methyl group, an ethyl group, anisopropyl group, an isobutyl group or a tert-butyl group.

Alkenyl and alkenylene radicals as well as alkynyl radicals can also bestraight-chain or branched. Examples of alkenyl radicals are vinyl,1-propenyl, alkyl, butenyl, 3-methyl-2-butenyl, examples of alkenyleneradicals are vinylene or propenylene and examples of alkynyl radicalsare ethynyl, 1-propynyl or propargyl.

Cycloalkyl radicals are, in particular, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl,cyclodecyl, cycloundecyl and cyclododecyl, but which can also besubstituted by, for example, (C₁-C₄)-alkyl. Examples of substitutedcycloalkyl radicals which may be mentioned are 4-methylcyclohexyl and2,3-dimethylcyclopentyl. The same applies to cycloalkylene radicals.

The 6- to 24-membered bicyclic and tricyclic radicals R¹⁶ are formallyobtained by abstraction of a hydrogen atom from bicyclic systems ortricyclic systems. The bicyclic systems and tricyclic systems on whichthey are based can contain only carbon atoms as ring members, i. e. theycan be bicycloalkanes or tricycloalkanes, but they can also contain one,two, three or four identical or different heteroatoms from the groupconsisting of nitrogen, oxygen and sulfur, i. e. they can be aza-, oxa-and thiabicyclo- and -tricycloalkanes. If heteroatoms are present,preferably one or two heteroatoms, in particular nitrogen or oxygenatoms, are present. The heteroatoms can assume any desired positions inthe bi- or tricyclic structure; they can be located in the bridges, orin the case of nitrogen atoms, also at the bridgeheads. Both thebicyclo- and tricycloalkanes and their heterocyclic analogs can becompletely saturated or can contain one or more double bonds. Theypreferably contain one or two double bonds or, in particular, arecompletely saturated. Both the bicyclo- and tricycloalkanes and theheterocyclic analogs and both the saturated and the unsaturatedrepresentatives can be unsubstituted or substituted in any desiredsuitable positions by one or more oxo groups and/or one or moreidentical or different (C₁-C₄)-alkyl groups, for example methyl orisopropyl groups, preferably methyl groups. The free bond of the bi- ortricyclic radical can be located in any desired position of themolecule; the radical can thus be bonded via a bridgehead atom or anatom in a bridge. The free bond can also be located in any desiredstereochemical position, for example in an exo or an endo position.

Examples of parent structures of bicyclic ring systems from which abicyclic radical can be derived are norbornane (=bicyclo[2.2.1]heptane),bicyclo[2.2.2]octane and bicyclo[3.2.1]octane, examples of unsaturatedor substituted systems or systems containing heteroatoms are7-azabicyclo[2.2.1]-heptane, bicyclo[2.2.2]oct-5-ene and camphor(=1,7,7-trimethyl-2-oxobicyclo[2.2.1]heptane).

Examples of systems from which a tricyclic radical can be derived aretwistane (=tricyclo[4.4.0.0^(3.8)]decane), adamantane(=tricyclo[3.3.1.1^(3.7)]-decane), noradamantane(=tricyclo[3.3.1.0^(3.7)]nonane), tricyclo[2.2.1.0^(2.6)]-heptane,tricyclo[5.3.2.0^(4.9)]dodecane, tricyclo[5.4.0.0^(2.9)]undecane ortricyclo[5.5.1.0^(3.11)]tridecane.

Preferably, bicyclic or tricyclic radicals representing R¹⁶ are derivedfrom bridged bicyclic systems or tricyclic systems, i.e. from systems inwhich rings together have two or more than two atoms. Bicyclic ortricyclic radicals having 6 to 18 ring members are additionallypreferred, particularly preferably those having 7 to 12 ring members.

Specifically particularly preferred bi- and tricyclic radicals are the2-norbornyl radical, both that with the free bond in the exo positionand also that with the free bond in the endo position, the2-bicyclo[3.2.1]octyl radical, the 1-adamantyl radical, the 2-adamantylradical and the noradamantyl radical, for example the 3-noradamantylradical. The 1- and the 2-adamantyl radicals are moreover preferred.

(C₆-C₁₄)-aryl groups are, for example, phenyl, naphthyl, biphenylyl,anthryl or fluorenyl, where 1-naphthyl, 2-naphthyl and in particularphenyl are preferred. Aryl radicals, in particular phenyl radicals, canbe mono- or polysubstituted, preferably mono-, di- or trisubstituted, byidentical or different radicals from the group consisting of(C₁-C₈)-alkyl, in particular (C₁-C₄)-alkyl, (C₁-C₈)-alkoxy, inparticular (C₁-C₄)-alkoxy, halogen, nitro, amino, trifluoromethyl,hydroxyl, methylenedioxy, ethylenedioxy, cyano, hydroxycarbonyl,aminocarbonyl, (C₁-C₄)-alkoxycarbonyl, phenyl, phenoxy, benzyl,benzyloxy, (R⁸O)₂P(O), (R⁸O)₂P(O)—O—, tetrazolyl. The same applies, forexample, to radicals such as aralkyl or arylcarbonyl. Aralkyl radicalsare, in particular, benzyl as well as 1- and 2-naphthylmethyl, 2-, 3-and 4-biphenylylmethyl and 9-fluorenylmethyl which can also besubstituted. Substituted aralkyl radicals are, for example, benzyl andnaphthylmethyl substituted in the aryl moiety by one or more(C₁-C₈)-alkyl radicals, in particular (C₁-C₄)-alkyl radicals, forexample 2-, 3- and 4-methylbenzyl, 4-isobutylbenzyl, 4-tert-butylbenzyl,4-octylbenzyl, 3,5-dimethylbenzyl, pentamethylbenzyl, 2-, 3-, 4-, 5-,6-, 7- and 8-methyl-1-naphthylmethyl, 1-, 3-, 4-, 5-, 6-, 7- and8-methyl-2-naphthylmethyl, or benzyl and naphthylmethyl substituted inthe aryl moiety by one or more (C₁-C₈)-alkoxy radicals, in particular(C₁-C₄)-alkoxy radicals, for example 4-methoxybenzyl,4-neopentyloxybenzyl, 3,5-dimethoxybenzyl, 3,4-methylenedioxybenzyl,2,3,4-trimethoxybenzyl, further 2-, 3- and 4-nitrobenzyl, halobenzyl,for example 2-, 3- and 4-chloro- and 2-, 3- and 4-fluorobenzyl,3,4-dichlorobenzyl, pentafluorobenzyl, trifluoromethylbenzyl, forexample 3- and 4-trifluoromethylbenzyl or3,5-bis(trifluoromethyl)benzyl. Substituted aralkyl radicals, however,can also have different substituents. Examples of pyridyl are 2-pyridyl,3-pyridyl and 4-pyridyl.

In monosubstituted phenyl radicals, the substituent can be located inthe 2-, the 3- or the 4-position, the 3- and the 4-positions beingpreferred. If phenyl is disubstituted, the substituents can be in the1,2-, 1,3- or 1,4-position relative to one another. Disubstituted phenylcan thus be substituted in the 2,3-position, the 2,4-position, the2,5-position, the 2,6-position, the 3,4-position or the 3,5-position,relative to the linkage site. Preferably, in disubstituted phenylradicals the two substituents are arranged in the 3-position and the4-position, relative to the linkage site. In trisubstituted phenylradicals the substituents can be located, for example, in the2,3,4-position, the 2,3,5-position, the 2,4,5-position, the2,4,6-position, the 2,3,6-position or the 3,4,5-position. The sameapplies for phenylene radicals which, for example, can be present as1,4-phenylene or as 1,3-phenylene.

Phenylene-(C₁-C₆)-alkyl is, in particular, phenylenemethyl (—C₆H₄—CH₂—)and phenyleneethyl, (C₁-C₆)-alkylenephenyl is, in particular,methylenephenyl (—CH₂—C₆H₄—). Phenylene-(C₂-C₆)-alkenyl is, inparticular, phenyleneethenyl and phenylenepropenyl.

Heteroaryl is a mono- or polycyclic aromatic radical having 5 to 14 ringmembers, which contains 1 to 5 heteroatoms as ring members. Examples ofheteroatoms are N, O and S. If several heteroatoms are contained, thesecan be identical or different. Heteroaryl radicals can also be mono- orpolysubstituted, preferably mono-, di- or trisubstituted, by identicalor different radicals from the group consisting of (C₁-C₈)-alkyl, inparticular (C₁-C₄)-alkyl, (C₁-C₈)-alkoxy, in particular (C₁-C₄)-alkoxy,halogen, nitro, amino, trifluoromethyl, hydroxyl, methylenedioxy,ethylenedioxy, cyano, hydroxycarbonyl, aminocarbonyl,(C₁-C₄)-alkoxycarbonyl, phenyl, phenoxy, benzyl, benzyloxy, (R⁸O)₂P(O),(R⁸O)₂P(O)—O—, tetrazolyl. Preferably, heteroaryl is a mono- or bicyclicaromatic radical which contains 1, 2, 3 or 4, in particular 1 to 3,identical or different heteroatoms from the group consisting of N, O andS and which can be substituted by 1, 2, 3 or 4, in particular 1 to 3,identical or different substituents from the group consisting of(C₁-C₆)-alkyl, (C₁-C₆)-alkoxy, fluorine, chlorine, nitro, amino,trifluoromethyl, hydroxyl, (C₁-C₄)-alkoxycarbonyl, phenyl, phenoxy,benzyloxy and benzyl. Particularly preferably, heteroaryl is a mono- orbicyclic aromatic radical having 5 to 10 ring members, in particular a5- to 6-membered monocyclic aromatic radical which contains 1, 2 or 3,in particular 1 or 2, identical or different heteroatoms from the groupconsisting of N, O and S and can be substituted by 1 or 2 identical ordifferent substituents from the group consisting of (C₁-C₄)-alkyl,(C₁-C₄)-alkoxy, phenyl, phenoxy, benzyloxy and benzyl.

Heterocyclic rings of the formula

which can represent the group R¹, can be completely saturated in thering or can contain one or more double bonds. In addition to thesubstituents in the groups Q¹ and Q³, these heterocyclic rings canadditionally carry one or more further, identical or different radicalsR²¹ and/or halogen atoms as substituents. The meanings —C(R²¹)(—)— and—N(—)— contained in the definition of Q³ are to be understood as meaningthat two of the three free bonds of the carbon atom or of the nitrogenatom are directed toward the adjacent ring members and the third freebond is directed toward the group A, such that in this case theheterocyclic ring is thus bonded to the group A via the group Q³. If theheterocyclic ring is fused to the ring system in the group A via twoadjacent atoms of the ring system, a condensed ring system is present.The fusion can take place via the group Q³ and the adjacent carbon atomor via any two desired adjacent carbon atoms. Examples of condensed ringsystems of this type are the radicals

Heterocycles which represent the mono- or bicyclic 5- to 12-memberedheterocyclic rings mentioned in the definition of R⁵ can be aromatic orpartially or completely saturated and can be substituted, in particularon a nitrogen atom, by (C₁-C₇)-alkyl, for example methyl or ethyl,phenyl or phenyl-(C₁-C₄)-alkyl, for example benzyl, and/or on one ormore carbon atoms by (C₁-C₄)-alkyl, halogen, hydroxyl, (C₁-C₄)-alkoxy,for example methoxy, phenyl-(C₁-C₄)-alkoxy, for example benzyloxy, oroxo.

Examples of heterocycles on which the group heteroaryl or the mono- orbicyclic 5- to 12-membered heterocyclic ring can be based are pyrrole,furan, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole,isothiazole, tetrazole, pyridine, pyrazine, pyrimidine, indole,isoindole, indazole, phthalazine, quinoline, isoquinoline, quinoxaline,quinazoline, cinnoline, β-carboline or benzo-fused, cyclopenta-,cyclohexa- or cyclohepta-fused derivatives of these heterocycles.Nitrogen heterocycles can also be present as N-oxides.

Radicals which can represent heteroaryl or the radical of a mono- orbicyclic 5- to 12-membered heterocyclic ring are, for example, 2- or3-pyrrolyl, phenylpyrrolyl, for example 4- or 5-phenyl-2-pyrrolyl,2-furyl, 2-thienyl, 4-imidazolyl, methylimidazolyl, for example1-methyl-2-, 4- or -5-imidazolyl, 1,3-thiazol-2-yl, 2-, 3- or 4-pyridyl,2-, 3- or 4-pyridyl-N-oxide, 2-pyrazinyl, 2-, 4- or 5-pyrimidinyl, 2-,3- or 5-indolyl, substituted 2-indolyl, for example 1-methyl-,5-methyl-, 5-methoxy-, 5-benzyloxy-, 5-Chloro or 4,5-dimethyl-2-indolyl,1-benzyl-2- or -3-indolyl, 4,5,6,7-tetrahydro-2-indolyl,cyclohepta[b]-5-pyrrolyl, 2-, 3- or 4-quinolyl, 1-, 3- or 4-isoquinolyl,1-oxo-1,2-dihydro-3-isoquinolyl, 2-quinoxalinyl, 2-benzofuranyl,2-benzothienyl, 2-benzoxazolyl or benzothiazolyl or, as radicals ofpartially hydrogenated or completely hydrogenated heterocyclic rings,for example also dihydropyridinyl, pyrrolidinyl, for example 2- or3-(N-methylpyrrolidinyl), piperazinyl, morpholinyl, thiomorpholinyl,tetrahydrothienyl, benzodioxolanyl.

Heterocyclic radicals representing the radical Het can be unsubstitutedon carbon atoms and/or ring nitrogen atoms or monosubstituted orpolysubstituted, for example disubstituted, trisubstituted,tetrasubstituted or pentasubstituted, by identical or differentsubstituents.

Carbon atoms can be substituted, for example, by (C₁-C₈)-alkyl, inparticular (C₁-C₄)-alkyl, (C₁-C₈)-alkoxy, in particular (C₁-C₄)-alkoxy,halogen, nitro, amino, trifluoromethyl, hydroxyl, oxo, methylenedioxy,cyano, hydroxycarbonyl, aminocarbonyl, (C₁-C₄)-alkoxycarbonyl, phenyl,phenoxy, benzyl, benzyloxy, (R⁸O)₂P(O), (R⁸O)₂P(O)—O—, tetrazolyl.Sulfur atoms can be oxidized to the sulfoxide or to the sulfone.Examples of the radical Het are 1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl,1-tetrazolyl, 1-dihydropyridin-1-yl, tetrahydropyridin-1-yl,1-pyrrolidinyl, 1-piperidinyl, 1-piperazinyl, 4-substituted1-piperazinyl, 4-morpholinyl, 4-thiomorpholinyl,1-oxo-4-thiomorpholinyl, 1,1-dioxothiomorpholinyl, perhydroazepin-1-yl,2,5-dimethyl-1-pyrrolyl, 2,6-dimethyl-1-piperidinyl,3,3-dimethyl-4-morpholinyl,4-isopropyl-2,2,6,6-tetramethyl-1-piperazinyl, 4-acetyl-1-piperazinyl,4-ethoxycarbonyl-1-piperazinyl.

Halogen is fluorine, chlorine, bromine or iodine, in particular fluorineor chlorine.

Natural or unnatural amino acids can be present in all stereochemicalforms, if chiral, for example in the D- or L-form or in the form of amixture of stereoisomers, for example in the form of a racemate. α-Aminoacids and β-amino acids are preferred, particularly preferred areα-amino acids. Examples of suitable amino acids which may be mentionedare (cf. Houben-Weyl, Methoden der organischen Chemie [Methods oforganic chemistry], Volume 15/1 and 15/2, Georg Thieme Verlag,Stuttgart, 1974):

Aad, Abu, γAbu, ABz, 2ABz, εAca, Ach, Acp, Adpd, Ahb, Aib, βAib, Ala,βAla, ΔAla, Alg, All, Ama, Amt, Ape, Apm, Apr, Arg, Asn, Asp, Asu, Aze,Azi, Bai, Bph, Can, Cit, Cys, (Cys)₂, Cyta, Daad, Dab, Dadd, Dap, Dapm,Dasu, Djen, Dpa, Dtc, Fel, Gln, Glu, Gly, Guv, hAla, hArg, hCys, hGln,hGlu, His, hMle, hLeu, hLys, hMet, hPhe, hpro, hSer, hThr, hTrp, hTyr,Hyl, Hyp, 3Hyp, Ile, Ise, Iva, Kyn, Lant, Lcn, Leu, Lsg, Lys, βLys,ΔLys, Met, Mim, Min, nArg, Nle, Nva, Oly, Om, Pan, Pec, Pen, Phe, Phg,Pic, Pro, ΔPro, Pse, Pya, Pyr, Pza, Qin, Ros, Sar, Sec, Sem, Ser, Thi,βThi, Thr, Thy, Thx, Tia, Tle, Tly, Trp, Trta, Tyr, Val,tert-butylglycine (Tbg), neopentylglycine (Npg), cyclohexylglycine(Chg), cyclohexylalanine (Cha), 2-thienylalanine (Thia),2,2-diphenylaminoacetic acid, 2-(p-tolyl)-2-phenylaminoacetic acid,2-(p-chlorophenyl)-amino acetic acid.

As customary in peptide chemistry, the radical of an amino acid, iminoacid or azaamino acid or of a dipeptide is obtained from thecorresponding amino acid, imino acid or azaamino acid or the dipeptideby formally removing a hydrogen atom from the N-terminal amino group orfrom the imino group or formally removing the hydroxyl group from thecarboxylic acid group. Amino acid side chains are understood as meaningside chains of natural or unnatural amino acids. Azaamino acids arenatural or unnatural amino acids in which a CH unit is replaced by anitrogen atom, for example in α-amino acids the central unit

Suitable radicals of an imino acid are, in particular, radicals ofheterocycles from the following group: pyrrolidine-2-carboxylic acid;piperidine-2-carboxylic acid; 12,3,4-tetrahydroisoquinoline-3-carboxylic acid;decahydroisoquinoline-3-carboxylic acid; octahydroindole-2-carboxylicacid; decahydroquinoline-2-carboxylic acid;octahydrocyclopenta[b]pyrrole-2-carboxylic acid;2-azabicyclo[2.2.2]octane-3-carboxylic acid;2-azabicyclo[2.2.1]heptane-3-carboxylic acid;2-azabicyclo[3.1.0]hexane-3-carboxylic acid;2-azaspiro[4.4]nonane-3-carboxylic acid;2-azaspiro[4.5]decane-3-carboxylic acid;spiro(bicyclo[2.2.1]heptane)-2,3-pyrrolidine-5-carboxylic acid;spiro(bicyclo[2.2.2]octane)-2,3-pyrrolidine-5-carboxylic acid;2-azatricyclo[4.3.0.1^(6.9)]decane-3-carboxylic acid;decahydrocyclohepta[b]pyrrole-2-carboxylic acid;decahydrocycloocta[c]pyrrole-2-carboxylic acid;octahydrocyclopenta[c]pyrrole-2-carboxylic acid;octahydroisoindole-1-carboxylic acid;2,3,3a,4,6a-hexahydrocyclopenta[b]pyrrole-2-carboxylic acid;2,3,3a,4,5,7a-hexahydroindole-2-Carboxylic acid;tetrahydrothiazole-4-carboxylic acid; isoxazolidine-3-carboxylic acid;pyrazolidine-3-carboxylic acid, hydroxypyrrolidine-2-carboxylic acid,all of which can optionally be substituted (see following formulae):

The heterocycles on which the abovementioned radicals are based aredisclosed, for example, in U.S. Pat. No. 4,344,949; U.S. Pat. No.4,374,847; U.S. Pat. No. 4,350,704; EP-A 29,488; EP-A 31,741; EP-A46,953; EP-A 49,605; EP-A 49,658; EP-A 50,800; EP-A 51,020; EP-A 52,870;EP-A 79,022; EP-A 84,164; EP-A 89,637; EP-A 90,341; EP-A 90,362; EP-A105,102; EP-A 109,020; EP-A 111,873; EP-A 271,865 and EP-A 344,682.

Dipeptides can contain natural or unnatural amino acids, imino acids aswell as azaamino acids as structural units. The natural or unnaturalamino acids, imino acids, azaamino acids and dipeptides can further bepresent also as esters or amides, such as, for example, as the methylester, ethyl ester, isopropyl ester, isobutyl ester, tert-butyl ester,benzyl ester, unsubstituted amide, ethylamide, semicarbazide orω-amino-(C₂-C₈)-alkylamide.

Functional groups of the amino acids, imino acids and dipeptides can bepresent in protected form. Suitable protective groups such as, forexample, urethane protective groups, carboxyl protective groups and sidechain protective groups are described in Hubbuch, Kontakte (Merck) 1979,No. 3, pages 14 to 23, and in Büllesbach, Kontakte (Merck) 1980, No. 1,pages 23 to 35. The following may be mentioned in particular: Aloc,Pyoc, Fmoc, Tcboc, Z, Boc, Ddz, Bpoc, Adoc, Msc, Moc, Z(NO₂),Z(Hal_(n)), Bobz, Iboc, Adpoc, Mboc, Acm, tert-butyl, OBzl, ONbzl,OMbzl, Bzl, Mob, Pic, Trt.

Physiologically tolerable salts of the compounds of the formula I are,in particular, pharmaceutically utilizable or nontoxic salts.

Such salts are formed, for example, from compounds of the formula Iwhich contain acidic groups, for example carboxylic acid or sulfonicacid or phosphonic acid groups, with inorganic bases, for example alkalimetal or alkaline earth metal compounds or ammonia. The salts of thecompounds of the formula I can thus be, for example, sodium, potassium,magnesium, calcium or ammonium salts. Salts of compounds of the formulaI with physiologically tolerable organic bases can also be formed, forexample with physiologically tolerable organic amines such astriethylamine, ethanolamine or tris(2-hydroxyethyl)amine.

Compounds of the formula I which contain basic groups, for example anamino group or a guanidino group, form salts with inorganic acids, suchas, for example, hydrochloric acid, sulfuric acid or phosphoric acid,and with organic carboxylic or sulfonic acids, such as, for example,acetic acid, citric acid, benzoic acid, maleic acid, fumaric acid,tartaric acid, methanesulfonic acid or p-toluenesulfonic acid.

Salts can be obtained from the compounds of the formula I by customarymethods known to the person skilled in the art, for example bycombination with an organic or inorganic acid or base in a solvent ordispersant, or alternatively from other salts by anion exchange orcation exchange.

The compounds of the formula I can be present in stereoisomeric forms.If the compounds of the formula I contain one or more centers ofasymmetry, these can independently of one another have the Sconfiguration or the R configuration. The invention includes allpossible stereoisomers, for example enantiomers and diastereomers, andmixtures of two or more stereoisomeric forms, for example mixtures ofenantiomers and/or diastereomers, in all ratios. The invention thusrelates to enantiomers in enantiomerically pure form, both as levo- andas dextrorotatory antipodes, in the form of racemates and in the form ofmixtures of the two enantiomers in all ratios. If cis/trans isomerism ispresent, the invention relates to both the cis form and the trans formand mixtures of these forms.

The compounds of the formula I according to the invention can moreovercontain mobile hydrogen atoms, i.e. can be present in various tautomericforms. The present invention also relates to all these tautomers. Thepresent invention furthermore includes all solvates of compounds of theformula I, for example hydrates or adducts with alcohols, as well asderivatives of the compounds of the formula I, for example esters,prodrugs and metabolites which act like the compounds of the formula I.

The individual structural elements in the formula I preferably have thefollowing meanings.

W is preferably R¹—A—C(R¹³).

A is preferably methylene, ethylene, trimethylene, tetramethylene,pentamethylene, cyclohexylene, phenylene, methylenephenyl,methylenephenylmethyl, phenylenemethyl or phenyleneethyl.

Y is preferably a carbonyl group.

Z is preferably N(R⁰).

B is preferably methylene, ethylene, trimethylene, tetramethylene,vinylene, phenylene or substituted methylene or ethylene. B isparticularly preferably a bivalent methylene radical or ethylene radical(=1,2-ethylene), where each of these radicals can be unsubstituted orsubstituted and in particular is substituted. Very particularlypreferably, B is a substituted or unsubstituted methylene radical, inparticular a substituted methylene radical. If a bivalent methyleneradical or ethylene radical (=1,2-ethylene) representing B issubstituted, it is preferably substituted by a radical from the groupconsisting of (C₁-C₈)-alkyl, (C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl,(C₃-C₈)-cycloalkyl, in particular (C₅-C₆)-cycloalkyl,(C₃-C₈)-cycloalkyl-(C₁-C₄)-alkyl, in particular(C₅-C₆)-cycloalkyl-(C₁-C₄)-alkyl, optionally substituted (C₆-C₁₀)-aryl,(C₆-C₁₀)-aryl-(C₁-C₄)-alkyl optionally substituted in the aryl radical,optionally substituted heteroaryl or heteroaryl-(C₁-C₄)-alkyl optionallysubstituted in the heteroaryl radical, and it is particularly preferablysubstituted by (C₁-C₈)-alkyl, i.e. by a straight-chain or branched alkylradical having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms.

D is preferably C(R²)(R³).

E is preferably R¹⁰CO.

R is preferably hydrogen, (C₁-C₆)-alkyl or benzyl, in particularhydrogen, methyl or ethyl.

R⁰ is preferably (C₁-C₈)-alkyl, (C₃-C₁₂)-cycloalkyl,(C₃-C₁₂)-cycloalkyl-(C₁-C₈)-alkyl, optionally substituted (C₆-C₁₄)-aryl,(C₆-C₁₄)-aryl-(C₁-C₈)-alkyl optionally substituted in the aryl radical,optionally substituted heteroaryl or heteroaryl-(C₁-C₈)-alkyl optionallysubstituted in the heteroaryl radical, particularly preferablyoptionally substituted (C₆-C₁₄)-aryl, (C₆-C₁₄)-aryl-(C₁-C₈)-alkyloptionally substituted in the aryl radical or heteroaryl-(C₁-C₈)-alkyloptionally substituted in the heteroaryl radical, very particularlypreferably optionally substituted (C₆-C₁₄)-aryl-(C₁-C₄)-alkyl optionallysubstituted in the aryl radical or heteroaryl-(C₁-C₄)-alkyl optionallysubstituted in the heteroaryl radical, moreover preferably(C₆-C₁₄)-aryl-(C₁-C₄)-alkyl optionally substituted in the aryl radical.It is specifically preferred if R⁰ is biphenylylmethyl, naphthylmethylor benzyl, each of which is unsubstituted or mono- or polysubstituted inthe aryl radical.

R¹ is preferably one of the radicals —S(O)—N(R²¹)—R²⁸,—S(O)₂—N(R²¹)—R²⁸, —O—C(O)—R²¹, —O—C(O)—OR²², —O—C(O)—N(R²¹)—R²⁸,—O—C(S)—N(R²¹)—R²⁸, —O—S(O)₂—N(R²¹)—R²⁸, —O—S(O)—N(R²¹)—R²⁸,—N(R²⁹)—C(O)—OR²², —N(R²⁸)—C(S)R²¹, —N(R²⁸)—C(O)—N(R²¹)—R²⁸,—N(R²⁸)—C(S)—N(R²¹)—R²⁸, —N(R²⁸)—S(O)₂—R²², N(R²⁸)—S(O)—R²²,—N(R²⁸)—S(O)₂—OR²¹, —N(R²⁸)—S(O)—OR²¹, —N(R²⁸)—S(O)₂—N(R²¹)—R²⁸,—N(R²⁸)—S(O)—N(R²¹)—R²⁸, —C(S)—R²¹, —C(S)—N(R²¹)—R²⁸ or cyano or theradical of an optionally substituted, 5- to 14-membered, mono- orpolycyclic, saturated or unsaturated heterocyclic ring of the formula

in which

Q¹ is —C(R²¹)₂—, ═C(R²¹)—, —N(R²⁸)—, —O— or —S—;

Q² is —S(O)— or —S(O)₂—;

Q³ is —C(R²¹)₂—, C(R²¹)—, —N(R²⁸)—, —O—, —S—, —C(R²¹)(—)— or —N(—)—,

where the heterocyclic ring can be bonded to the group A via the freebond in the groups —C(R²¹)(—)— or —N(—)— representing Q³ or via anyother desired ring carbon atom and where, if the heterocyclic ring isbonded to a ring system contained in the group A, the heterocyclic ringcan also be fused via two adjacent atoms to the ring system in the groupA. Particularly preferably, R¹ is one of the radicals —O—C(O)—R²¹,—O—C(O)—OR²², —O—C(O)— N(R²¹)—R²⁸, —N(R²⁹)—C(O)—OR²²,—N(R²⁸)—C(O)—N(R²¹)—R²⁸, —N(R²⁸)—C(S)—N(R²¹)—R²⁸ or cyano.

R² is preferably hydrogen or (C₁-C₈)-alkyl.

R³ is preferably (C₁-C₈)-alkyl, optionally substituted (C₆-C₁₄)-aryl,(C₆-C₁₄)-aryl-(C₁-C₈)-alkyl optionally substituted in the aryl radical,(C₃-C₈)-cycloalkyl, (C₂-C₈)-alkenyl, (C₂-C₈)-alkynyl, pyridyl, R¹¹NH,R⁴CO, COOR⁴, CON(CH₃)R⁴, CONHR⁴, CSNHR⁴, COOR¹⁵, CON(CH₃)R¹⁵ or CONHR¹⁵,particularly preferably optionally substituted (C₆-C₁₄)-aryl, R¹¹NH,CON(CH₃)R⁴ or CONHR⁴.

R⁴ is preferably (C₁-C₈)-alkyl which can optionally be substituted asindicated in the definition of R⁴, particularly preferably (C₁-C₈)-alkylwhich is substituted by one or two of the radicals indicated in thedefinition of R⁴;

R¹¹ is preferably hydrogen, R^(12a), R^(12a)—CO, H—CO, R^(12a)—O—CO,R^(12b)—CO, R^(12b)—CS or R^(12a)—S(O)₂, particularly preferablyhydrogen, R^(12a), R^(12a)—CO, R^(12a)—O—CO, R^(12b)—CO, R^(12b)—CS orR^(12a)—S(O)₂, in particular a radical from the group consisting ofhydrogen, (C₁-C₁₈)-alkyl, R^(12c)CO, optionally substituted(C₆-C₁₄)-aryl-S(O)₂, (C₁-C₁₈)-alkyl-S(O)₂, (C₆-C₁₄)-aryl-(C₁-C₈)-alkyloptionally substituted in the aryl radical, R⁹NHS(O)₂ and R¹⁵, whereR^(c) is hydrogen, (C₁-C₁₈)-alkyl, (C₂-C₈)-alkenyl, (C₂-C₈)-alkynyl,optionally substituted (C₆-C₁₄)-aryl, (C₁-C₁₈)-alkoxy,(C₆-C₁₄)-aryl-(C₁-C₈)-alkoxy, which can also be substituted in the arylradical, optionally substituted (C₆-C₁₄)-aryloxy, amino or mono- ordi-((C₁-C₁₈)-alkyl)-amino, the radical R¹⁵ or the radical R¹⁵—O—. Veryparticularly preferably, R¹¹ is R^(12a), R^(12a)—CO, R^(12a)—O—CO,R^(12b)—CO, R^(12b)—CS or R^(12a)—S(O)₂, moreover particularlypreferably for R^(12a), R^(12a)—CO, R^(12a)—O—CO, R^(12b)—CO orR^(12a)—S(O)₂.

R^(12a) is preferably (C₁-C₁₀)-alkyl, (C₂-C₈)-alkenyl, (C₂-C₈)-alkynyl,(C₃-C₁₂)-cycloalkyl, (C₃-C₁₂)-cycloalkyl-(C₁-C₈)-alkyl, optionallysubstituted (C₆-C₁₄)-aryl, (C₆-C₁₄)-aryl-(C₁-C₈)-alkyl optionallysubstituted in the aryl radical, optionally substituted heteroaryl,heteroaryl-(C₁-C₈)-alkyl optionally substituted in the heteroarylradical or the radical R¹⁵.

R^(12b) is preferably R^(12a)—NH.

R¹³ is preferably hydrogen, (C₁-C₆)-alkyl, (C₆-C₁₄)-aryl-(C₁-C₈)-alkyloptionally substituted in the aryl radical or (C₃-C₈)-cycloalkyl,particularly preferably hydrogen or in particular (C₁-C₆)-alkyl,(C₃-C₈)-cycloalkyl or benzyl, where a very particularly preferred alkylradical representing R¹³ is the methyl radical.

R¹⁵ is preferably R¹⁶—(C₁-C₃)-alkyl or R¹⁶, particularly preferablyR¹⁶—(C₁)-alkyl or R¹⁶. Moreover, when R³ is COOR¹⁵, R¹⁵ is preferablythe exo-2-norbornyl radical, the endo-2-norbornyl radical or thebicyclo[3.2.1]octyl radical, and when R³ is CONHR¹⁵, R¹⁵ is theexo-2-norbornyl radical, the endo-2-norbornyl radical, the3-noradamantyl radical and in particular the 1-adamantyl radical, the2-adamantyl radical, the 1-adamantylmethyl radical or the2-adamantylmethyl radical.

R¹⁶ is preferably a 7- to 12-membered bridged bicyclic or tricyclicradical, which is saturated or partially unsaturated and which can alsocontain one to four identical or different heteroatoms from the groupconsisting of nitrogen, oxygen and sulfur and which can also besubstituted by one or more identical or different substituents from thegroup consisting of (C₁-C₄)-alkyl and oxo.

Het is preferably the radical of a 5- to 10-membered, saturatedmonocyclic or polycyclic heterocycle bonded via a nitrogen atom, whichcan contain one or two identical or different additional ringheteroatoms from the group consisting of oxygen, nitrogen and sulfur andcan optionally be substituted on carbon atoms and on ring nitrogenatoms, where there can be identical or different radicals R^(h), R^(h)COor R^(h)O—CO as substituents on additional ring nitrogen atoms.Particularly preferably, Het is a heterocycle of the type which containsno additional ring heteroatom or which contains one additional ringheteroatom from the group consisting of nitrogen, oxygen and sulfur,very particularly preferably Het is the radical of a 5-, 6- or7-membered, saturated monocyclic heterocycle bonded via a nitrogen atom,which contains no additional ring heteroatom or which contains oneadditional ring heteroatom from the group consisting of nitrogen, oxygenand sulfur, where in these cases too the radical Het can beunsubstituted or can be substituted on carbon atoms and/or on additionalring nitrogen atoms.

b, c and d preferably independently of one another are 1.

e, g and h preferably independently of one another are the numbers 0, 1,2 or 3.

Preferred compounds of the formula I are those in which, simultaneously

-   W is R¹—A—C(R¹³) or R¹—A—CH═C;-   Y is a carbonyl, thiocarbonyl or methylene group;-   Z is N(R⁰), oxygen, sulfur or a methylene group;-   A is a bivalent radical from the group consisting of    (C₁-C₆)-alkylene, (C₃-C₁₂)-cycloalkylene,    (C₁-C₆)-alkylene-(C₃-C₁₂)-cycloalkyl, phenylene,    phenylene-(C₁-C₆)-alkyl, (C₁-C₆)-alkylenephenyl,    (C₁-C₆)-alkylenephenyl-(C₁-C₆)-alkyl, phenylene-(C₂-C₆)-alkenyl or a    bivalent radical of a 5- or 6-membered saturated or unsaturated ring    which can contain 1 or 2 nitrogen atoms and can be mono- or    disubstituted by (C₁-C₆)-alkyl or doubly bonded oxygen or sulfur, or    is a direct bond;-   B is a bivalent radical from the group consisting of    (C₁-C₆)-alkylene, (C₂-C₆)-alkenylene, phenylene,    phenylene-(C₁-C₃)-alkyl, (C₁-C₃)-alkylene-phenyl;-   D is C(R²)(R³), N(R³) or CH═C(R³);-   E is tetrazolyl, (R⁸O)₂P(O), HOS(O)₂, R⁹NHS(O)₂ or R¹⁰CO;-   R and R⁰ independently of one another are hydrogen, (C₁-C₈)-alkyl,    (C₃-C₁₂)-cycloalkyl, (C₃-C₁₂)-cycloalkyl-(C₁-C₈)-alkyl, optionally    substituted (C₆-C₁₄)-aryl, (C₆-C₁₄)-aryl-(C₁-C₈)-alkyl optionally    substituted in the aryl radical, optionally substituted heteroaryl    or heteroaryl-(C₁-C₈)-alkyl optionally substituted in the heteroaryl    radical, where alkyl radicals can be mono- or polysubstituted by    fluorine;-   R¹ is one of the radicals —S—R²¹, —S—S—R²¹, —S(O)—R²², —S(O)₂—R²²,    —S—OR²¹, —S(O)—OR²¹, —S(O)₂—OR²¹, —S—N(R²¹)—R²⁸, —S(O)—N(R²¹)—R²⁸,    —S(O)₂—N(R²¹)—R²⁸, —S—C(O)—R²¹, —S—C(O)—OR²², —S—C(S)—SR²²,    —S—C(O)—N(R²¹)—R²⁸, —S—C(S)—N(R²¹)—R²⁸, —O—C(O)—R²¹, —O—C(S)—R²¹,    —O—C(O)—OR²², —O—C(O)—N(R²¹)—R²⁸, —O—C(S)—N(R²¹)—R²⁸, —O—S(O)₂—OR²¹,    —O—S(O)—OR²¹, —O—S(O)₂—N(R²¹)—R²⁸, —O—S(O)—N(R²¹)—R²⁸, —O—S(O)₂—R²²,    —O—S(O)—R²², —O—P(O)(OR²¹)₂, —O—P(O)(OR²¹)—N(R²¹)—R²⁸,    —O—P(O)(N(R²¹)—R²⁸)₂, —N(R²⁹)—C(O)—OR²², —N(R²⁸)—C(O)—SR²²,    —N(R²⁸)—C(S)—OR²², —N(R²⁸)—C(S)—SR²², —N(R²⁸)—C(S)—R²¹,    —N(R²⁸)—C(O)—N(R²¹)—R²⁸, —N(R²⁸)—C(S)—N(R²¹)—R²⁸, —N(R²⁸)—S(O)₂—R²²,    —N(R²⁸)—S(O)—R²², —N(R²⁸)—S(O)₂—OR²¹, —N(R²⁸)—S(O)—OR²¹,    —N(R²⁸)—S(O)₂—N(R²¹)—R²⁸, —N(R²⁸)—S(O)—N(R²¹)—R²⁸,    —N(R²⁸)—P(O)(OR²¹)₂, —N(R²⁸)—P(O)(OR²¹)—N(R²¹)—R²⁸,    —N(R²⁸)—P(O)(N(R²¹)—R²⁸)₂, —N(R²⁸)—P(O)(R²²)—OR²¹,    —N(R²⁸)—P(O)(R²²)—N(R²¹)—R²⁸, —N(R²⁸)—P(O)(R₂₂)₂, —P(O)(OR²¹)₂,    —P(O)(OR²¹)—N(R²¹)—R²⁸, —P(O)(N(R²¹)—R²⁸)₂, —P(O)(R²²)—OR²¹,    —P(O)(R²²)—N(R²¹)—R²⁸, —P(O)(R²²)₂, —C(S)—R²¹, —C(S)—SR²¹,    —C(S)—N(R²¹)—R²⁸, cyano, halogen, nitro or methylenedioxy or the    radical of an optionally substituted, 5- to 14-membered, mono- or    polycyclic, saturated or unsaturated heterocyclic ring of the    formula-    in which    -   Q¹ is —C(R²¹)₂—, ═C(R²¹)—, —N(R²⁸)—, —O— or —S—;    -   Q² is —S(O)— or —S(O)₂—;    -   Q³ is —C(R²¹)₂—, ═C(R²¹)—, —N(R²⁸)—, —O—, —S—, —C(R²¹)(—)— or        —N(—)—,    -   where the heterocyclic ring can be bonded to the group A via the        free bond in the groups —C(R²¹)(—)— or —N(—)— representing Q³ or        via any other desired ring carbon atom and where, if the        heterocyclic ring is bonded to a ring system contained in the        group A, the heterocyclic ring can also be fused via two        adjacent atoms to the ring system in the group A;-   R² is hydrogen, (C₁-C₈)-alkyl, optionally substituted (C₆-C₁₄)-aryl,    (C₆-C₁₄)-aryl-(C₁-C₈)-alkyl optionally substituted in the aryl    radical or (C₃-C₈)-cycloalkyl;-   R³ is hydrogen, (C₁-C₈)-alkyl, optionally substituted (C₆-C₁₄)-aryl,    (C₆-C₁₄)-aryl-(C₁-C₈)-alkyl optionally substituted in the aryl    radical, (C₃-C₈)-cycloalkyl, (C₂-C₈)-alkenyl, (C₂-C₈)-alkynyl,    (C₂-C₈)-alkenylcarbonyl, (C₂-C₈)-alkynylcarbonyl, pyridyl, R¹¹NH,    R⁴CO, COOR⁴, CON(CH₃)R⁴, CONHR⁴, CSNHR⁴, COOR¹⁵, CON(CH₃)R¹⁵ or    CONHR¹⁵;-   R⁴ is hydrogen or (C₁-C₂₈)-alkyl which can optionally be mono- or    polysubstituted by identical or different radicals from the group    consisting of hydroxyl, hydroxycarbonyl, aminocarbonyl, mono- or    di-((C₁-C₁₈)-alkyl)aminocarbonyl, amino-(C₂-C₁₈)-alkylaminocarbonyl,    amino-(C₁-C₃)-alkylphenyl-(C₁-C₃)-alkylaminocarbonyl,    (C₁-C₁₈)-alkylcarbonylamino-(C₁-C₃)-alkylphenyl-(C₁-C₃)-alkylaminocarbonyl,    (C₁-C₁₈)-alkylcarbonylamino-(C₂-C₁₈)-alkylaminocarbonyl,    (C₆-C₁₄)-aryl-(C₁-C₈)-alkoxycarbonyl which can also be substituted    in the aryl radical, amino, mercapto, (C₁-C₁₈)-alkoxy,    (C₁-C₁₈)-alkoxycarbonyl, optionally substituted (C₃-C₈)-cycloalkyl,    HOS(O)₂—(C₁-C₃)-alkyl, R⁹NHS(O)₂—(C₁-C₃)-alkyl,    (R⁸O)₂P(O)—(C₁-C₃)-alkyl, tetrazolyl-(C₁-C₃)-alkyl, halogen, nitro,    trifluoromethyl or the radical R⁵;-   R⁵ is optionally substituted (C₆-C₁₄)-aryl,    (C₆-C₁₄)-aryl-(C₁-C₈)-alkyl optionally substituted in the aryl    radical, a mono- or bicyclic 5- to 12-membered heterocyclic ring    which can be aromatic, partially hydrogenated or completely    hydrogenated and which can contain one, two or three identical or    different heteroatoms from the group consisting of nitrogen, oxygen    and sulfur, a radical R⁶ or a radical R⁶CO—, where the aryl radical    and, independently thereof, the heterocyclic radical can be mono- or    polysubstituted by identical or different radicals from the group    consisting of (C₁-C₁₈)-alkyl, (C₁-C₁₈)-alkoxy, halogen, nitro, amino    or trifluoromethyl;-   R⁶ is R⁷R⁸N, R⁷O or R⁷S or an amino acid side chain, a natural or    unnatural amino acid, imino acid, optionally N—(C₁-C₈)-alkylated or    N—((C₆-C₁₄)-aryl-(C₁-C₈)-alkylated) azaamino acid or a dipeptide    radical which can also be substituted in the aryl radical and/or in    which the peptide bond can be reduced to —NH—CH₂—, and their esters    and amides, where hydrogen or hydroxymethyl can optionally stand in    place of free functional groups and/or where free functional groups    can be protected by protective groups customary in peptide    chemistry;-   R⁷ is hydrogen, (C₁-C₁₈)-alkyl, (C₆-C₁₄)-aryl-(C₁-C₈)-alkyl,    (C₁-C₁₈)-alkylcarbonyl, (C₁-C₁₈)-alkoxycarbonyl,    (C₆-C₁₄)-arylcarbonyl, (C₆-C₁₄)-aryl-(C₁-C₈)-alkylcarbonyl or    (C₆-C₁₄)-aryl-(C₁-C₁₈)-alkyloxycarbonyl, where the alkyl groups can    optionally be substituted by an amino group and/or where the aryl    radicals can be mono- or polysubstituted, preferably    monosubstituted, by identical or different radicals from the group    consisting of (C₁-C₈)-alkyl, (C₁-C₈)-alkoxy, halogen, nitro, amino    and trifluoromethyl, or is a natural or unnatural amino acid, imino    acid, optionally N—(C₁-C₈)-alkylated or    N—((C₆-C₁₄)-aryl-(C₁-C₈)-alkylated) azaamino acid or a dipeptide    radical which can also be substituted in the aryl radical and/or in    which the peptide bond can be reduced to —NH—CH₂—;-   R⁸ is hydrogen, (C₁-C₁₈)-alkyl, optionally substituted (C₆-C₁₄)-aryl    or (C₆-C₁₄)-aryl-(C₁-C₈)-alkyl which can also be substituted in the    aryl radical;-   R⁹ is hydrogen, aminocarbonyl, (C₁-C₁₈)-alkylaminocarbonyl,    (C₃-C₈)-cycloalkylaminocarbonyl, optionally substituted    (C₆-C₁₄)-arylaminocarbonyl, (C₁-C₁₈)-alkyl, optionally substituted    (C₆-C₁₄)-aryl or (C₃-C₈)-cycloalkyl;-   R¹⁰ is hydroxyl, (C₁-C₁₈)-alkoxy, (C₆-C₁₄)-aryl-(C₁-C₈)-alkoxy which    can also be substituted in the aryl radical, optionally substituted    (C₆-C₁₄)-aryloxy, amino or mono- or di-((C₁-C₁₈)-alkyl)amino;-   R¹¹ is hydrogen, (C₁-C₁₈)-alkyl, R¹²CO, optionally substituted    (C₆-C₁₄)-aryl-S(O)₂, (C₁-C₁₈)-alkyl-S(O)₂,    (C₆-C₁₄)-aryl-(C₁-C₈)-alkyl optionally substituted in the aryl    radical, R⁹NHS(O)₂ or the radical R¹⁵;-   R¹² is hydrogen, (C₁-C₁₈)-alkyl, (C₂-C₈)-alkenyl, (C₂-C₈)-alkynyl,    optionally substituted (C₆-C₁₄)-aryl, (C₁-C₁₈)-alkoxy,    (C₆-C₁₄)-aryl-(C₁-C₈)-alkoxy which can also be substituted in the    aryl radical, optionally substituted (C₆-C₁₄)-aryloxy, amino or    mono- or di-((C₁-C₁₈)-alkyl)amino, the radical R¹⁵ or the radical    R¹⁵—O—;-   R¹³ is hydrogen, (C₁-C₆)-alkyl, (C₆-C₁₄)-aryl-(C₁-C₈)-alkyl    optionally substituted in the aryl radical or (C₃-C₈)-cycloalkyl;-   R¹⁵ is R¹⁶—(C₁-C₆)-alkyl or R¹⁶;-   R¹⁶ is a 6- to 24-membered bicyclic or tricyclic radical which is    saturated or partially unsaturated and which can also contain one to    four identical or different heteroatoms from the group consisting of    nitrogen, oxygen and sulfur and which can also be substituted by one    or more identical or different substituents from the group    consisting of (C₁-C₄)-alkyl and oxo;-   R²¹ is hydrogen, (C₁-C₈)-alkyl, hydroxy-(C₁-C₈)-alkyl,    (C₂-C₈)-alkenyl, (C₃-C₁₂)-cycloalkyl,    (C₃-C₁₂)-cycloalkyl-(C₁-C₈)-alkyl, optionally substituted    (C₆-C₁₄)-aryl, (C₆-C₁₄)-aryl-(C₁-C₈)-alkyl optionally substituted in    the aryl radical, optionally substituted heteroaryl or    heteroaryl-(C₁-C₈)-alkyl optionally substituted in the heteroaryl    radical, where alkyl radicals can also be monosubstituted or    polysubstituted by fluorine and the radicals R²¹ can be identical or    different if they occur two or more times;-   R²² is (C₁-C₈)-alkyl, hydroxy-(C₁-C₈)-alkyl, (C₂-C₈)-alkenyl,    (C₃-C₁₂)-cycloalkyl, (C₃-C₁₂)-cycloalkyl-(C₁-C₈)-alkyl, optionally    substituted (C₆-C₁₄)-aryl, (C₆-C₁₄)-aryl-(C₁-C₈)-alkyl optionally    substituted in the aryl radical, optionally substituted heteroaryl    or heteroaryl-(C₁-C₈)-alkyl optionally substituted in the heteroaryl    radical, where alkyl radicals can be monosubstituted or    polysubstituted by fluorine and the radicals R²² can be identical or    different if they occur two or more times;-   R²⁸ is one of the radicals R²¹—, R²¹N(R²¹)—, R²¹C(O)—, R²²O—C(O)—,    R²¹N(R²¹)—C(O)— or R²¹N(R²¹)—C(═N(R²¹))—;-   R²⁹ is one of the radicals R²²—, R²¹N(R²¹)—, R²¹C(O)—, R²²O—C(O)—,    R²¹N(R²¹)—C(O)— or R²¹N(R²¹)—C(═N(R²¹))—;-   b, c, d and f independently of one another are 0 or 1, but cannot    all simultaneously be 0;-   e, g and h independently of one another are 0, 1, 2, 3, 4, 5 or 6;-   in all their stereoisomeric forms and mixtures thereof in any ratio,    and their physiologically tolerable salts,

where, if simultaneously W is 4-cyanophenyl-C(R¹³), Y is a carbonylgroup, Z is NR^(0a), B is an unsubstituted methylene group, R is R^(a),b, c and d are 1 and e, f and g are 0, then D cannot beC(R^(2a))(R^(3a)), where

-   R^(0a), R^(a) and R^(2a) independently of one another are hydrogen,    (C₁-C₈)-alkyl, optionally substituted (C₆-C₁₄)-aryl,    (C₆-C₁₄)-aryl-(C₁-C₈)-alkyl optionally substituted in the aryl    radical or (C₃-C₈)-cycloalkyl and-   R^(3a) is hydrogen, (C₁-C₈)-alkyl, optionally substituted    (C₆-C₁₄)-aryl, (C₆-C₁₄)-aryl-(C₁-C₈)-alkyl optionally substituted in    the aryl radical, (C₃-C₈)-cycloalkyl or 2-, 3- or 4-pyridyl.

Particularly preferred compounds of the formula I are those in whichsimultaneously W is R¹—A—CH═C and therein A is a phenylene radical or amethylenephenyl radical, or W is R¹—A—C(R¹³) and therein A is a bivalentradical from the group consisting of methylene, ethylene, trimethylene,tetramethylene, pentamethylene, cyclohexylene, phenylene,phenylenemethyl, methylenephenyl, methylenephenylmethyl;

B is a bivalent radical from the group consisting of methylene,ethylene, trimethylene, tetramethylene, vinylene, phenylene, orsubstitued methylene or ethylene;

E is R¹⁰CO;

R is hydrogen, (C₁-C₆)-alkyl or benzyl;

R⁰ is (C₁-C₈)-alkyl, (C₃-C₈)-cycloalkyl, optionally substituted(C₆-C₁₄)-aryl or (C₆-C₁₄)-aryl-(C₁-C₈)-alkyl optionally substituted inthe aryl radical;

R¹ is preferably one of the radicals —S(O)—N(R²¹)—R²⁸,—S(O)₂—N(R²¹)—R²⁸, —O—C(O)—R²¹, —O—C(O)—OR²², —O—C(O)—N(R²¹)—R²⁸,—O—C(S)—N(R²¹)—R²⁸, —O—S(O)₂—N(R²¹)—R²⁸, —O—S(O)—N(R²¹)—R²⁸,—N(R²⁹)—C(O)—OR²², —N(R²⁸)—C(S)—R²¹, —N(R²⁸)—C(O)—N(R²¹)—R²⁸,—N(R²⁸)—C(S)—N(R²¹)—R²⁸, —N(R²⁸)—S(O)₂—R²², —N(R²⁸)—S(O)—R²²,—N(R²⁸)—S(O)₂—OR²¹, —N(R²⁸)—S(O)—OR²¹, —N(R²⁸)—S(O)₂—N(R²¹)—R²⁸,—N(R²⁸)—S(O)—N(R²¹)—R²⁸, —C(S)—R²¹, —C(S)—N(R²¹)—R²⁸ or cyano or theradical of an optionally substituted, 5- to 14-membered, mono- orpolycyclic, saturated or unsaturated heterocyclic ring of the formula

in which

Q¹ is —C(R²¹)₂—, ═C(R²¹)—, —N(R²⁸)—, —O— or —S—;

Q² is —S(O)— or —S(O)₂—;

Q³ is —C(R²¹)₂—, ═C(R²¹)—, —N(R²⁸)—, —O—, —S—, —C(R²¹) (—)— or —N(—)—,

where the heterocyclic ring can be bonded to the group A via the freebond in the groups —C(R²¹)(—)— or —N(—)— representing Q³ or via anyother desired ring carbon atom and where, if the heterocyclic ring isbonded to a ring system contained in the group A, the heterocyclic ringcan also be fused via two adjacent atoms to the ring system in the groupA;

R² is hydrogen or (C₁-C₈)-alkyl;

R³ is (C₁-C₈)-alkyl, optionally substituted (C₆-C₁₄)-aryl,(C₆-C₁₄)-aryl-(C₁-C₈)-alkyl, (C₃-C₈)-cycloalkyl, (C₂-C₈)-alkenyl,(C₂-C₈)-alkynyl, pyridyl, R¹¹NH, R⁴CO, COOR⁴, CONHR⁴, CSNHR⁴, COOR¹⁵ andCONHR¹⁵;

and e, g and h independently of one another are the numbers 0, 1, 2 or3;

in all their stereoisomeric forms and mixtures thereof in any ratio, andtheir physiologically tolerable salts.

Very particularly preferred compounds of the formula I are those inwhich W is R¹—A—C(R¹³) and R¹³ is (C₁-C₆)-alkyl,(C₆-C₁₄)-aryl-(C₁-C₈)-alkyl optionally substituted in the aryl radicalor (C₃-C₈)-cycloalkyl;

in all their stereoisomeric forms and mixtures thereof in any ratio, andtheir physiologically tolerable salts.

A series of specifically preferred compounds of the formula I are thosein which R³ is optionally substituted (C₆-C₁₄)-aryl, COOR⁴, R¹¹NH orCONHR¹⁴, where —NHR¹⁴ is the radical of an α-amino acid, itsω-amino-(C₂-C₈)-alkylamide, its (C₁-C₈)-alkyl ester, its(C₆-C₁₄)-aryl-(C₁-C₄)-alkyl ester, or its derivative in which thecarboxylic acid group is converted into the group Het-CO, in all theirstereoisomeric forms and mixtures thereof in any ratio, and theirphysiologically tolerable salts. The radical of an α-amino acid —NHR¹⁴is formally obtained by abstraction of a hydrogen atom from the aminogroup of the amino acid. It is specifically preferred in this series ifR³ is CONHR⁴, where —NHR⁴ is the radical of the α-amino acids valine,lysine, phenylglycine, phenylalanine or tryptophan or their(C₁-C₈)-alkyl esters, (C₆-C₁₄)-aryl-(C₁-C₄)-alkyl esters or Het-COderivative.

Moreover preferred compounds of the formula I in this series are thosein which simultaneously

W is R¹—A—C(R¹³);

Y is a carbonyl group;

Z is N(R⁰);

A is ethylene, trimethylene, tetramethylene, pentamethylene,cyclohexylene, phenylene, phenylenemethyl, methylenephenyl ormethylenephenylmethyl;

B is an unsubstituted or substituted methylene radical;

D is C(R²)(R³);

E is R¹⁰CO;

R is hydrogen or (C₁-C₄)-alkyl, in particular hydrogen, methyl or ethyl;

R⁰ is (C₁-C₈)-alkyl, (C₃-C₈)-cycloalkyl, optionally substituted(C₆-C₁₄)-aryl or (C₆-C₁₄)-aryl-(C₁-C₈)-alkyl optionally substituted inthe aryl radical;

R¹ is one of the radicals —O—C(O)R²¹, —O—C(O)—OR²², —O—C(O)—N(R²¹)—R²⁸,—N(R²⁹)—C(O)—OR¹², —N(R²⁸)—C(O)—N(R²¹)—R²⁸, —N(R²⁸)—C(S)—N(R²¹)—R²⁸ orcyano;

R² is hydrogen;

R³ is the radical CONHR⁴;

R⁴ is methyl which is substituted by hydroxycarbonyl and a radical fromthe group consisting of (C₁-C₄)-alkyl, phenyl and benzyl, or is methylwhich is substituted by (C₁-C₈)-alkoxycarbonyl, preferably(C₁-C₄)-alkoxycarbonyl, and a radical from the group consisting of(C₁-C₄)-alkyl, phenyl and benzyl, or is methyl which is substituted byHet-CO and a radical from the group consisting of (C₁-C₄)-alkyl, phenyland benzyl;

R¹⁰ is hydroxyl or (C₁-C₈)-alkoxy, preferably (C₁-C₄)-alkoxy;

R¹³ is (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl or benzyl, in particularmethyl;

b, c and d are 1 and e, f and g are 0;

h is 1 or 2, preferably 1;

in all their stereoisomeric forms and mixtures thereof in any ratio, andtheir physiologically tolerable salts.

If —NHR⁴ is a (C₁-C₈)-alkyl ester of an α-amino acid or R⁴ contains analkoxycarbonyl radical, the methyl, ethyl, isopropyl, isobutyl ortert-butyl ester is preferred, if —NHR⁴ is a (C₆-C₁₄)-aryl-(C₁-C₄)-alkylester of an α-amino acid, the benzyl ester is preferred.

A further series of specifically preferred compounds of the formula Iare those compounds in which simultaneously

W is R¹-A-CH═C and therein A is a phenylene radical or a methylenephenylradical, or W is R¹-A-C(R¹³) and therein A is a bivalent radical fromthe group consisting of methylene, ethylene, trimethylene,tetramethylene, pentamethylene, cyclohexylene, phenylene,phenylenemethyl, methylenephenyl, methylenephenylmethyl;

B is a bivalent radical from the group consisting of methylene,ethylene, trimethylene, tetramethylene, vinylene, phenylene orsubstituted methylene or ethylene;

E is R¹⁰CO;

R is hydrogen or (C₁-C₆)-alkyl;

R⁰ is (C₁-C₈)-alkyl, (C₃-C₈)-cycloalkyl, optionally substituted(C₆-C₁₄)-aryl or (C₆-C₁₄)-aryl-(C₁-C₈)-alkyl optionally substituted inthe aryl radical;

R¹ is preferably one of the radicals —S(O)—N(R²¹)—R²⁸,—S(O)₂—N(R²¹)—R²⁸, —O—C(O)—R²¹, —O—C(O)—OR²², —O—C(O)—N(R²¹)—R²⁸,—O—C(S)—N(R²¹)—R²⁸, —O—S(O)₂—N(R²¹)—R²⁸, —O—S(O)—N(R²¹)—R²⁸,—N(R²⁹)—C(O)—OR²², —N(R²⁸)—C(S)—R²¹, —N(R²⁸)—C(O)—N(R²¹)—R²⁸,—N(R²⁸)—C(S)—N(R²¹)—R²⁸, —N(R²⁸)—S(O)₂—R²², —N(R²⁸)—S(O)—R²²,—N(R²⁸)—S(O)₂—OR²¹, —N(R²⁸)—S(O)—OR²¹, —N(R²⁸)—S(O)₂—N(R²¹)—R²⁸,—N(R²⁸)—S(O)—N(R²¹)—R²⁸, —C(S)—R²¹, —C(S)—N(R²¹)—R²⁸ or cyano or theradical of an optionally substituted, 5- to 14-membered, mono- orpolycyclic, saturated or unsaturated heterocyclic ring of the formula

in which

Q¹ is —C(R²¹)₂—, ═C(R²¹)—, —N(R²⁸)—, —O— or —S—;

Q² is —S(O)— or —S(O)₂—;

Q³ is —C(R²¹)₂—, ═C(R²¹)—, —N(R²⁸)—, —O—, —S—, —C(R²¹)(—)— or —N(—)—,

where the heterocyclic ring can be bonded to the group A via the freebond in the groups —C(R²¹)(—)— or —N(—)— representing Q³ or via anyother desired ring carbon atom and where, if the heterocyclic ring isbonded to a ring system contained in the group A, the heterocyclic ringcan also be fused via two adjacent atoms to the ring system in the groupA;

R² is hydrogen or (C₁-C₈)-alkyl;

R³ is CONHR¹⁵ or CONHR⁴ where R⁴ herein is a (C₁-C₈)-alkyl radical whichis unsubstituted or substituted by one or more (C₆-C₁₄)-aryl radicals;

R¹⁵ is R¹⁶—(C₁-C₆)-alkyl or R¹⁶, where R¹⁶ is a 7- to 12-memberedbridged bicyclic or tricyclic radical which is saturated or partiallyunsaturated and which can also contain one to four identical ordifferent heteroatoms from the group consisting of nitrogen, oxygen andsulfur and which can also be substituted by one or more identical ordifferent substituents from the group consisting of (C₁-C₄)-alkyl andoxo, and in particular R¹⁵ is an adamantyl radical or an adamantylmethylradical;

and e, g and h independently of one another are the numbers 0, 1, 2 or 3and b, c and d are 1;

in all their stereoisomeric forms and mixtures thereof in any ratio, andtheir physiologically tolerable salts.

Moreover preferred compounds of the formula I in this series are thosein which simultaneously

W is R¹-A-C(R¹³);

Y is a carbonyl group;

Z is N(R⁰);

A is ethylene, trimethylene, tetramethylene, pentamethylene,cyclohexylene, phenylene, phenylenemethyl, methylenephenyl ormethylenephenylmethyl;

B is an unsubstituted or substituted methylene radical;

D is C(R²)(R³);

E is R¹⁰CO;

R is hydrogen or (C₁-C₄)-alkyl, in particular hydrogen, methyl or ethyl;

R⁰ is (C₁-C₈)-alkyl, (C₃-C₈)-cycloalkyl, optionally substituted(C₆-C₁₄)-aryl or (C₆-C₁₄)-aryl-(C₁-C₈)-alkyl optionally substituted inthe aryl radical;

R¹ is one of the radicals —O—C(O)—R²¹, —O—C(O)—OR²², —O—C(O)—N(R²¹)—R²⁸,—N(R²⁹)—C(O)—OR²², —N(R²⁸)—C(O)—N(R²¹)—R²⁸, —N(R²⁸)—C(S)—N(R²¹)—R²⁸ orcyano;

R² is hydrogen;

R³ is CONHR¹⁵ or CONHR⁴ where R⁴ herein is a (C₁-C₆)-alkyl radical whichis unsubstituted or substituted by one or more (C₆-C₁₀)-aryl radicals;

R¹⁰ is hydroxyl or (C₁-C₈)-alkoxy, preferably (C₁-C₄)-alkoxy;

R¹³ is (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl or benzyl, in particularmethyl;

R¹⁵ is an adamantyl radical or an adamantylmethyl radical;

b, c and d are 1 and e, f and g are 0;

h is 1 or 2, preferably 1;

in all their stereoisomeric forms and mixtures thereof in any ratio, andtheir physiologically tolerable salts.

Furthermore, a series of specifically preferred compounds of the formulaI are those in which simultaneously

W is R¹-A-C(R¹³);

Y is a carbonyl group;

Z is N(R⁰);

A is ethylene, trimethylene, tetramethylene, pentamethylene,cyclohexylene, phenylene, phenylenemethyl, methylenephenyl,methylenephenylmethyl;

B is an unsubstituted or substituted methylene radical or ethyleneradical;

D is C(R²)(R³);

E is R¹⁰CO;

R is hydrogen or (C₁-C₄)-alkyl, in particular hydrogen, methyl or ethyl;

R⁰ is (C₁-C₈)-alkyl, (C₃-C₈)-cycloalkyl, optionally substituted(C₆-C₁₄)-aryl or (C₆-C₁₄)-aryl-(C₁-C₈)-alkyl which is optionallysubstituted in the aryl radical;

R¹ is preferably one of the radicals —S(O)—N(R²¹)—R²⁸,—S(O)₂—N(R²¹)—R²⁸, —O—C(O)—R²¹, —O—C(O)—OR²², —O—C(O)—N(R²¹)—R²⁸,—O—C(S)—N(R²¹)—R²⁸, —O—S(O)₂—N(R²¹)—R²⁸, —O—S(O)—N(R²¹)—R²⁸,—N(R²⁹)—C(O)—OR²², —N(R²⁸)—C(S)—R²¹, —N(R²⁸)—C(O)—N(R²¹)—R²⁸,—N(R²⁸)—C(S)—N(R²¹)—R²⁸, —N(R²⁸)—S(O)₂—R²², —N(R²⁸)—S(O)—R²²,—N(R²⁸)—S(O)₂—OR²¹, —N(R²⁸)—S(O)—OR²¹, —N(R²⁸)—S(O)₂—N(R²¹)—R²⁸,—N(R²⁸)—S(O)—N(R²¹)—R²⁸, —C(S)—R²¹, —C(S)—N(R²¹)—R²⁸ or cyano or theradical of an optionally substituted, 5- to 14-membered, mono- orpolycyclic, saturated or unsaturated heterocyclic ring of the formula

in which

Q¹ is —C(R²¹)₂—, ═C(R²¹)—, —N(R²⁸)—, —O— or —S—;

Q² is —S(O)— or —S(O)₂—;

Q³ is —C(R²¹)₂—, ═C(R²¹)—, —N(R²⁸)—, —O—, —S—, —C(R²¹)(—)— or —N(—)—,

where the heterocyclic ring can be bonded to the group A via the freebond in the groups —C(R²¹)(—)— or —N(—)— representing Q³ or via anyother desired ring carbon atom and where, if the heterocyclic ring isbonded to a ring system contained in the group A, the heterocyclic ringcan also be fused via two adjacent atoms to the ring system in the groupA;

R² is hydrogen;

R³ is an unsubstituted phenyl radical or naphthyl radical, a phenylradical or naphthyl radical substituted by one, two or three identicalor different radicals from the group consisting of (C₁-C₄)-alkyl,(C₁-C₄)-alkoxy, hydroxyl, halogen, trifluoromethyl, nitro,methylenedioxy, ethylenedioxy, hydroxycarbonyl, (C₁-C₄)-alkoxycarbonyl,aminocarbonyl, cyano, phenyl, phenoxy and benzyloxy, a pyridyl radical,a (C₁-C₄)-alkyl radical, a (C₂-C₄)-alkenyl radical, a (C₂-C₄)-alkynylradical or a (C₅-C₆)-cycloalkyl radical, and in particular R³ is anunsubstituted or substituted phenyl radical or naphthyl radical;

R¹⁰ is hydroxyl or (C₁-C₈)-alkoxy, in particular (C₁-C₄)-alkoxy, andpreferably R¹⁰ is a radical from the group consisting of hydroxyl,methoxy, ethoxy, propoxy and isopropoxy;

R¹³ is (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl or benzyl, in particularmethyl;

b, c and d are 1 and e, f and g are 0;

h is 1 or 2, preferably 1;

in all their stereoisomeric forms and mixtures thereof in any ratio, andtheir physiologically tolerable salts.

Finally, a series of specifically preferred compounds of the formula Iare those compounds in which simultaneously

W is R¹-A-C(R¹³);

Y is a carbonyl group;

Z is N(R⁰);

A is ethylene, trimethylene, tetramethylene, pentamethylene,cyclohexylene, phenylene, phenylenemethyl, methylenephenyl,methylenephenylmethyl;

B is an unsubstituted or substituted methylene radical or ethyleneradical;

D is C(R²)(R³);

E is R¹⁰CO;

R is hydrogen or (C₁-C₄)-alkyl, in particular hydrogen, methyl or ethyl;

R⁰ is (C₁-C₈)-alkyl, (C₃-C₈)-cycloalkyl, optionally substituted(C₆-C₁₄)-aryl or (C₆-C₁₄)-aryl-(C₁-C₈)-alkyl optionally substituted inthe aryl radical;

R¹ is preferably one of the radicals —S(O)—N(R²¹)—R²⁸,—S(O)₂—N(R²¹)—R²⁸, —O—C(O)—R²¹, —O—C(O)—OR²², —O—C(O)—N(R²¹)—R²⁸,—O—C(S)—N(R²¹)—R²⁸, —O—S(O)₂—N(R²¹)—R²⁸, —O—S(O)—N(R²¹)—R²⁸,—N(R²⁹)—C(O)—OR²², —N(R²⁸)—C(S)—R²¹, —N(R²⁸)—C(O)—N(R²¹)—R²⁸,—N(R²⁸)—C(S)—N(R²¹)—R²⁸, —N(R²⁸)—S(O)₂—R²², —N(R²⁸)—S(O)—R²²,—N(R²⁸)—S(O)₂—OR²¹, —N(R²⁸)—S(O)—OR²¹, —N(R²⁸)—S(O)₂—N(R²¹)—R²⁸,—N(R²⁸)—S(O)—N(R²¹)—R²⁸, —C(S)—R²¹, —C(S)—N(R²¹)—R²⁸ or cyano or theradical of an optionally substituted, 5- to 14-membered, mono- orpolycyclic, saturated or unsaturated heterocyclic ring of the formula

in which

Q¹ is —C(R²¹)₂—, ═C(R²¹)—, —N(R²⁸)—, —O— or —S—;

Q² is —S(O)— or —S(O)₂—;

Q³ is —C(R²¹)₂—, ═C(R²¹)—, —N(R²⁸)—, —O—, —S—, —C(R²¹)(—)— or —N(—)—,

where the heterocyclic ring can be bonded to the group A via the freebond in the groups —C(R²¹)(—)— or —N(—)— representing Q³ or via anyother desired ring carbon atom and where, if the heterocyclic ring isbonded to a ring system contained in the group A, the heterocyclic ringcan also be fused via two adjacent atoms to the ring system in the groupA;

R² is hydrogen;

R³ is R¹¹NH;

R¹⁰ is hydroxyl or (C₁-C₈)-alkoxy, in particular (C₁-C₄)-alkoxy, andpreferably R¹⁰ is a radical from the group consisting of hydroxyl,methoxy, ethoxy, propoxy and isopropoxy;

R¹³ is (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl or benzyl, in particularmethyl;

b, c, d and e are 1 and f and g are 0;

h is 0;

in all their stereoisomeric forms and mixtures thereof in any ratio, andtheir physiologically tolerable salts.

In this series, moreover preferred compounds of the formula I are thosein which R¹¹ is R^(12a), R^(12a)—CO, R^(12a)—O—CO, R^(12b)—CO,R^(12b)—CS or R^(12a)—S(O)₂, in particular R^(12a), R^(12a)—CO,R^(12a)—O—CO, R^(12b)—CO or R^(12a)—S(O)₂;

R^(12a) is (C₁-C₁₀)-alkyl, (C₂-C₈)-alkenyl, (C₂-C₈)alkynyl,(C₃-C₁₂)-cycloalkyl, (C₃-C₁₂)-cycloalkyl-(C₁-C₈)-alkyl, optionallysubstituted (C₆-C₁₄)-aryl, (C₆-C₁₄)-aryl-(C₁-C₈)-alkyl optionallysubstituted in the aryl radical, optionally substituted heteroaryl,heteroaryl-(C₁-C₈)-alkyl optionally substituted in the heteroarylradical or the radical R¹⁵;

R^(12b) is R^(12a)—NH;

in all their stereoisomeric forms and mixtures thereof in any ratio, andtheir physiologically tolerable salts.

Very specifically preferred compounds of the formula I are those inwhich a substituted methylene radical or substituted ethylene radicalrepresenting the group B carries as a substituent a radical from thegroup consisting of (C₁-C₈)-alkyl, (C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl,(C₃-C₈)-cycloalkyl, in particular (C₅-C₆)-cycloalkyl,(C₃-C₈)-cycloalkyl-(C₁-C₄)-alkyl, in particular(C₅-C₆)-cycloalkyl-(C₁-C₄)-alkyl, optionally substituted (C₆-C₁₀)-aryl,(C₆-C₁₀)-aryl-(C₁-C₄)-alkyl optionally substituted in the aryl radical,optionally substituted heteroaryl and heteroaryl-(C₁-C₄)-alkyloptionally substituted in the heteroaryl radical, in all theirstereoisomeric forms and mixtures thereof in any ratio, and theirphysiologically tolerable salts. Even more specifically preferredcompounds of the formula I are those in which B is an unsubstitutedmethylene radical or a methylene radical which is substituted by a(C₁-C₈)-alkyl radical, in particular by a (C₁-C₆)-alkyl radical, in alltheir stereoisomeric forms and mixtures thereof in any ratio, and theirphysiologically tolerable salts.

Generally, compounds of the formula I are preferred which have a uniformconfiguration at chiral centers, e.g. at the chiral carbon atomrepresenting D and at the center W in the 5-membered ring heterocycle inthe formula I.

The compounds of the formula I can be prepared, for example, by fragmentcondensation of a compound of the formula II

with a compound of the formula III,

where W, Y, Z, B, D, E, R and b, d, e, f, g, and h are defined asindicated above and G is hydroxycarbonyl, (C₁-C₆)-alkoxycarbonyl,activated carboxylic acid derivatives, such as acid chlorides or activeesters, or isocyanato.

For the condensation of the compounds of the formula II with those ofthe formula III, the coupling methods of peptide chemistry known per se(see, for example, Houben-Weyl, Methoden der Organischen Chemie,[Methods of organic chemistry], Volume 15/1 and 15/2, Georg ThiemeVerlag, Stuttgart, 1974) are advantageously used. To do this, as a ruleit is necessary that nonreacting amino groups present are protected byreversible protective groups during the condensation. The same appliesto carboxyl groups not participating in the reaction, which arepreferably present as (C₁-C₆)-alkyl, benzyl or tert-butyl esters. Aminogroup protection is unnecessary if the amino groups to be generated arestill present as nitro or cyano groups and are formed, for example, byhydrogenation only after the coupling. After the coupling, theprotective groups present are removed in a suitable manner. For example,NO₂ groups (guanidino protection), benzyloxycarbonyl groups and benzylesters can be removed by hydrogenation. The protective groups of thetert-butyl type are removed under acidic conditions, while the9-fluorenylmethyloxycarbonyl radical is removed by secondary amines.

Compounds of the formula II in which W is R¹-A-C(R¹³), Y is a carbonylgroup and Z is NR⁰ can be prepared, for example, by first reactingcompounds of the formula IV

in a Bucherer reaction to give compounds of the formula V,

in which just as in the formula IV R¹, R¹³ and A are defined asindicated above (H. T. Bucherer, V. A. Lieb, J. Prakt. Chem. 141(1934),5). Compounds of the formula VI,

in which R¹, R¹³, A, B and G are defined as indicated above can then beobtained by first reacting the compounds of the formula V, for example,with an alkylating reagent which introduces the radical —B—G into themolecule. The reaction of compounds of the formula VI with a secondreagent of the formula R⁰—LG, in which R⁰ has the meanings indicatedabove and LG is a nucleophilically substitutable leaving group, forexample halogen, in particular chlorine or bromine, (C₁-C₄)-alkoxy,optionally substituted phenoxy or a heterocyclic leaving group such as,for example, imidazolyl, leads to the corresponding compounds of theformula II. These reactions can be carried out analogously to knownmethods familiar to the person skilled in the art. Depending on theindividual case, it may be appropriate here, as in all steps in thesynthesis of the compounds of the formula I, temporarily to blockfunctional groups which could lead to side reactions or undesiredreactions by means of a protective group strategy adapted to thesynthesis problem, which is known to the person skilled in the art.

If W is R¹-A-CH═C, this structural element can be introduced, forexample, by condensing an aldehyde with a 5-membered ring heterocyclewhich contains a methylene group in the position corresponding to thegroup W analogously to known methods.

Compounds of the formula I in which the 5-membered ring heterocycle is adioxo- or thioxo-oxo-substituted imidazolidine ring in which W isR¹-A-C(R¹³) can also be obtained as follows:

by reaction of α-amino acids or N-substituted α-amino acids orpreferably their esters, for example the methyl, ethyl, tert-butyl orbenzyl esters, for example of a compound of the formula VII,

in which R⁰, R¹, R¹³ and A are defined as indicated above, with anisocyanate or isothiocyanate, for example, of the formula VIII,

in which B, D, E and R and also b, c, d, e, f, g and h are defined asindicated above and U is isocyanato or isothiocyanato, there areobtained urea or thiourea derivatives, for example of the formula IX

for which the definitions indicated above apply and in which V is oxygenor sulfur, and which by heating with acid are cyclized with hydrolysisof the ester functions to give compounds of the formula Ia

in which V is oxygen or sulfur, W is R¹-A-C(R¹³) and for which otherwisethe meanings indicated above apply. The cyclization of the compounds ofthe formula IX to the compounds of the formula Ia can also be carriedout by treatment with bases in inert solvents, for example by treatmentwith sodium hydride in an aprotic solvent such as dimethylformamide.

During the cyclization, guanidino groups can be blocked by protectivegroups, for example NO₂. Amino groups in the side chain can be presentin protected form or still as an NO₂ or cyano function which can laterbe reduced to the amino group or, in the case of the cyano group, canalso be converted into the formamidino group.

Compounds of the formula I in which the 5-membered ring heterocycle is adioxo- or thioxo-oxo-substituted imidazolidine ring in which W isR¹-A-C(R¹³) and c is 1 can also be obtained by reacting a compound ofthe formula VII with an isocyanate or isothiocyanate of the formula X

in which B, U and b are defined as indicated above for the formula VIIIand L is an alkoxy group, for example a (C₁-C₄)-alkoxy group such asmethoxy, ethoxy or tert-butoxy, a (C₆-C₁₄)-aryloxy group, for examplephenoxy, or a (C₆-C₁₄)-aryl-(C₁-C₄)-alkoxy group, for example benzyloxy.In this case, a compound of the formula XI

is obtained in which A, B, V, L, R⁰, R¹, R¹³ and b are defined asindicated above for the formulae IX and X, which is then cyclized underthe influence of an acid or of a base, such as described above for thecyclization of the compounds of the formula IX, to a compound of theformula XII

in which B, L, V, W, R⁰ and b are defined as indicated above for theformulae Ia and X. From the compound of the formula XII, a compound ofthe formula Ia is then obtained by hydrolysis of the group CO—L to givethe carboxylic acid COOH and subsequent coupling with a compound of theformula III, as described above for the coupling of the compounds of theformulae II and III. Here too, during the cyclization functional groupscan be present in protected form or in the form of precursors, forexample guanidino groups are blocked by NO₂ or amino groups are presentin protected form or still as an NO₂ or cyano function which can laterbe reduced to the amino group or, in the case of the cyano group, canalso be converted into the formamidino group.

A further method for the preparation of compounds of the formula Ia is,for example, the reaction of compounds of the formula XIII,

in which W is R¹-A-C(R¹³) and for which otherwise the definitionsindicated above apply, with phosgene, thiophosgene or correspondingequivalents (analogously to S. Goldschmidt and M. Wick, Liebigs Ann.Chem. 575 (1952), 217-231 and C. Tropp, Chem. Ber. 61 (1928),1431-1439).

A conversion of an amino function into a guanidino function can becarried out using the following reagents:

1. O-Methylisourea (S. Weiss and H. Krommer, Chemiker Zeitung 98 (1974),617-618)

2. S-Methylisothiourea (R. F. Borne, M. L. Forrester and I. W. Waters,J. Med. Chem. 20 (1977), 771-776)

3. Nitro-S-methylisothiourea (L. S. Hafner and R. E. Evans, J. Org.Chem. 24 (1959) 57)

4. Formamidinosulfonic acid (K. Kim, Y.-T. Lin and H. S. Mosher, Tetrah.Lett. 29 (1988), 3183-3186)

5. 3,5-Dimethyl-1-pyrazolylformamidinium nitrate (F. L. Scott, D. G.O'Donovan and J. Reilly, J. Amer. Chem. Soc. 75 (1953), 4053-4054)

6. N,N′-Di-tert-butyloxycarbonyl-S-methylisothiourea (R. J. Bergeron andJ. S. McManis, J. Org. Chem. 52 (1987), 1700-1703)

7. N-Alkoxycarbonyl-, N,N′-dialkoxycarbonyl-, N-alkylcarbonyl- andN,N′-dialkylcarbonyl-S-methylisothiourea (H. Wollweber, H. Kölling, E.Niemers, A. Widdig, P. Andrews, H.-P. Schulz and H. Thomas, Arzneim.Forsch./Drug Res. 34 (1984), 531-542).

With respect to the preparation of the compounds of the formula I, thedetails on the synthesis of the molecular structure which are containedin the following documents are fully incorporated by reference:WO-A-95/14008, German Patent Application 19515177.1 and WO-A-96/33976corresponding to it, and German Patent Application 19635522.2 and thePatent Applications corresponding to it, for example European PatentApplication 97103712.2 and U.S. patent application No. 08/821,253, whichare part of the present disclosure.

For the preparation of compounds of the formula I in which R¹ is —S—R²¹,the starting materials used can be the corresponding compounds of theformula IV in which R¹ is —S—R²¹. If compounds of the formula IV inwhich R¹ is a protected SH group are employed in the Bucherer reaction,compounds of the formula I in which R¹ is —SH are obtained after theremoval of the protective group. These compounds can in turn beconverted into compounds of the formula I in which R¹ is —S—R²¹ (withmeanings of R²¹ other than hydrogen) by introduction of the radical R²¹,or alternatively serve as intermediates for the preparation of othercompounds of the formula I in which the atom bonded to the group A ofthe radical R²¹ is a sulfur atom.

Compounds of the formula I in which R¹ is —S(O)₂—R²¹ can be prepared,for example, by oxidizing compounds of the formula I in which R¹ is—S—R²¹ to the sulfones according to methods known from the literature(cf. Houben-Weyl, Methoden der Organischen Chemie [Methods of OrganicChemistry], Vol. E12/2, Georg Thieme Verlag, Stuttgart 1985, p. 1058ff.), i.e. to the compounds of the formula I in which R¹ is —S(O)₂—R²¹.Correspondingly, compounds of the formula I in which R¹ is —S—R²¹ can beoxidized to the sulfoxides under suitable reaction conditions familiarto the person skilled in the art according to methods known per se (cf.Houben-Weyl, Methoden der Organischen Chemie, Vol. E11/1, Georg ThiemeVerlag, Stuttgart 1985, p. 702 ff.), i.e. to the compounds of theformula I in which R¹ is —S(O)—R²¹. If necessary, in the oxidations tothe sulfoxides or to the sulfones, oxidation-sensitive groups in themolecule are protected by suitable protective groups before carrying outthe oxidation.

Compounds of the formula I in which R¹ is —S(O)₂—OR²¹ or—S(O)₂—N(R²¹)—R²⁸ can be prepared, for example, by oxidizing compoundsof the formula I in which R¹ is —SH according to methods known from theliterature (cf. Houben-Weyl, Methoden der Organischen Chemie, Vol.E12/2, Georg Thieme Verlag, Stuttgart 1985, p. 1058 ff.) for thepreparation of sulfonic acid derivatives to compounds of the formula Iin which R¹ is —S(O)₂—OH. The compounds of the formula I in which R¹ is—S(O)₂—OR²¹ or —S(O)₂—N(R²¹)—R²⁸ can then be obtained from thesesulfonic acids directly or via corresponding sulfonyl halides byesterification or linkage of an amide bond.

Compounds of the formula I in which R¹ is —S(O)—OR² or —S(O)—N(R²¹)—R²⁸can be prepared, for example, by converting compounds of the formula Iin which R¹ is —SH into the corresponding sulfides, i.e. into the saltsin which R¹ is —S and the counterion is, for example, an alkali metalion or an alkaline earth metal ion, and then oxidizing these salts, forexample using meta-chloroperbenzoic acid, to the sulfinic acids, i.e. tothe compounds of the formula I in which R¹ is —S(O)—OH (cf. Houben-Weyl,Methoden der Organischen Chemie, Vol. E11/1, Georg Thieme Verlag,Stuttgart 1985, p. 618 ff.). The corresponding sulfinic acid esters andsulfinamides, i.e. the compounds of the formula I in which R¹ is—S(O)—OR²¹ or —S(O)—N(R²¹)—R²⁸, can be prepared from the sulfinic acidsby methods known per se.

If necessary, also in the preparation of sulfonic acid derivatives andsulfinic acid derivatives by oxidation, oxidation-sensitive groups inthe molecule are protected by suitable protective groups before carryingout the oxidation.

Apart from the methods mentioned, for the preparation of the compoundsof the formula I in which R¹ is —S(O)—R²², —S(O)₂—R²², —S(O)—OR²¹,—S(O)₂—OR²¹, —S(O)—N(R²¹)—R²⁸ or —S(O)₂—N(R²¹)—R²⁸ other processesdescribed in the literature for preparing such types of compounds cangenerally also be used (cf. Houben-Weyl, Methoden der OrganischenChemie, Georg Thieme Verlag, Stuttgart, Vol. E11/1, 1985, p. 618 ff. orVol. E11/2, 1985, p. 1055 ff.).

Compounds of the formula I in which R¹ is further sulfur-containinggroups, for example —N(R²⁸)—C(S)—OR²², —N(R²⁸)—C(S)—SR²²,—N(R²⁸)—C(S)—R²¹, —N(R²⁸)—S(O)₂—R²², —N(R²⁸)—S(O)—R²²,—N(R²⁸)—S(O)₂—OR²¹, —N(R²⁸)—S(O)—OR²¹, —N(R²⁸)—S(O)₂—N(R²¹)—R²⁸,—N(R²⁸)—S(O) —N(R²¹)—R²⁸, —O—C(S)—N(R²¹)—R²⁸, —O—S(O)₂—OR²¹,—O—S(O)—OR²¹, —O—S(O)₂—N(R²¹)—R²⁸, —O—S(O)—N(R²¹)—R²⁸, —O—S(O)₂—R²²,O—S(O)—R²², —C(S)—R²¹, —C(S)—N(R²¹)—R²⁸, can be synthesized fromsuitable precursors by methods known per se and described in theliterature (cf Houben-Weyl, Methoden der Organischen Chemie, Vol. E11/1and E11/2, Georg Thieme Verlag, Stuttgart 1985), the adaptation of theselected synthesis method to the particular target molecule presentingno problems to the person skilled in the art. This also applies tofurther methods for the preparation of compounds of the formula I inwhich R¹ is —S—R²¹.

The latter also applies to the preparation of the compounds of theformula I in which R¹ is one of the phosphorus-containing radicalsmentioned in the definition of R¹, for example a phosphonic acidderivative or a phosphoric acid derivative. These compounds can besynthesized analogously to methods known from the literature (cf.Houben-Weyl, Methoden der Organischen Chemie, Vol. E1 and E2, GeorgThieme Verlag, Stuttgart 1982) for the preparation of such compoundsfrom suitable precursors.

Compounds of the formula I in which R¹ is —N(R²⁸)—C(O)—NH—R²⁸ can beprepared, for example, by reacting the corresponding compounds of theformula I in which R¹ is —NH—R²⁸ with isocyanates of the formulaO—C═N—R²⁸ according to methods known from the literature (cf.Houben-Weyl, Methoden der Organischen Chemie, Vol. VIII, Georg ThiemeVerlag, Stuttgart 1952, p. 132). Analogously, compounds of the formula Iin which R¹ is —N(R²⁸)—C(S)—NH—R²⁸ can be prepared, for example, byreacting the corresponding compounds of the formula I in which R¹ is—NHR²⁸ with isothiocyanates of the formula S═C—N—R²⁸. Generally, for thepreparation of compounds of the formula I in which R¹ is—N(R²⁸)—C(O)—N(R²¹)—R²⁸ or —N(R²⁸)—C(S)—N(R²¹)—R²⁸, methods known fromthe literature for the preparation of ureas or thioureas can be used(cf. Houben-Weyl, Methoden der Organischen Chemie, Vol. VIII, GeorgThieme Verlag, Stuttgart 1952).

Compounds of the formula I in which R¹ is —N(R²⁹)—C(O)—OR²² can beprepared, for example, by reacting compounds of the formula I in whichR¹ is —NHR²⁹ with chlorocarbonic acid esters of the formula Cl—C(O)—OR²²according to methods known from the literature (cf. Houben-Weyl,Methoden der Organischen Chemie, Vol. VIII, Georg Thieme Verlag,Stuttgart 1952, p. 138). Generally, other methods known from theliterature can also be used for the preparation of compounds of theformula I in which R¹ is —N(R²⁹)—C(O)—OR²² (cf Houben-Weyl, Methoden derOrganischen Chemie, Vol. VIII, Georg Thieme Verlag, Stuttgart 1952).Compounds of the formula I in which R¹ is —N(R²⁸)—C(O)—SR²² can beprepared analogously.

Compounds of the formula I in which R¹ is —O—C(O)—NH—R²⁸ can beprepared, for example, by reacting compounds of the formula I in whichR¹ is —OH with isocyanates of the formula O═C═N—R²⁸ according to methodsknown from the literature (cf. Houben-Weyl, Methoden der OrganischenChemie, Vol. VIII, Georg Thieme Verlag, Stuttgart 1952, p. 141).Analogously, compounds of the formula I in which R¹ is —S—C(O)—NH—R²⁸can be prepared, for example, by reacting compounds of the formula I inwhich R¹ is —SH with isocyanates of the formula O═C═N—R²⁸. Analogouslyisothiocyanates of the formula S═C═N—R²⁸ can be reacted. Generally, forthe preparation of compounds of the formula I in which R¹ is—O—C(O)—N(R²¹)—R²⁸ or —S—C(O)—N(R²¹)—R²⁸, methods known from theliterature for the preparation of such carbonic acid derivatives can beused, for example reactions with carbamoyl halides.

Compounds of the formula I in which R¹ is —O—C(O)—R²¹ can be prepared,for example, by reacting compounds of the formula I in which R¹ is —OHaccording to methods known per se and described in the literature (cf.Houben-Weyl, Methoden der Organischen Chemie, Vol. VIII, Georg ThiemeVerlag, Stuttgart 1952, p. 508 ff.), for example, with reactivecarboxylic acid derivatives. Correspondingly, for example, compounds ofthe formula I in which R¹ is O—C(O)—OR²² can be obtained from compoundsof the formula I in which R¹ is —OH using suitable carbonic acidderivatives such as, for example, chlorocarbonic acid esters.

In accordance with the above details, the compounds of the formula I inwhich the radicals W, Z, Y, B, R, D, E and b, c, d, e, f, g and h havethe meanings indicated at the outset can also be employed asintermediates for the preparation of other compounds, in particularfurther pharmaceutical active compounds which are obtainable from thecompounds of the formula I, for example, by modification or introductionof radicals or functional groups.

The compounds of the formula I in which the radicals W, Z, Y, B, R, D, Eand b, c, d, e, f, g and h have the meanings indicated at the outset areantagonists of the adhesion receptor VLA-4 and/or inhibitors ofleucocyte adhesion. This applies to the same extent also to thecompounds already described in WO-A-96/33976, which are excludedaccording to the definition given at the outset of those compounds whichare claimed per se in the present application, but for which nopharmacological action or pharmaceutical use is described inWO-A-96/33976. The following details of the pharmacological action anduse also apply to the last-mentioned compounds. For the preparation ofthe last-mentioned compounds, reference is made to WO-A-96/33976 andGerman Patent Application 19515177.1, whose contents are inasmuch partof the present disclosure. With respect to the use of compounds and withrespect to pharmaceutical preparations, the present invention thusrelates on the one hand to the compounds of the formula I in which theradicals W, Z, Y, B, R, D, E and b, c, d, e, f, g and h have themeanings indicated at the outset, but on the other hand also to thecompounds which are excluded according to the definition of the claimedcompounds indicated at the outset and which are described inWO-A-96/33976. With respect to the use and pharmaceutical preparationdescribed in the following, the present invention thus relates tocompounds of the formula Ib,

in which

-   -   W is R¹-A-C(R¹³) or R¹-A-CH═C;    -   Y is a carbonyl, thiocarbonyl or methylene group;    -   Z is N(R⁰), oxygen, sulfur or a methylene group;    -   A is a bivalent radical from the group consisting of        (C₁-C₆)-alkylene, (C₃-C₁₂)-cycloalkylene,        (C₁-C₆)-alkylene-(C₃-C₁₂)-cycloalkyl, phenylene,        phenylene-(C₁-C₆)-alkyl, (C₁-C₆)-alkylenephenyl,        (C₁-C₆)-alkylenephenyl-(C₁-C₆)-alkyl, phenylene-(C₂-C₆)-alkenyl        or a bivalent radical of a 5- or 6-membered, saturated or        unsaturated ring which can contain 1 or 2 nitrogen atoms and can        be mono- or disubstituted by (C₁-C₆)-alkyl or doubly bonded        oxygen or sulfur or is a direct bond;    -   B is a bivalent radical from the group consisting of        (C₁-C₆)-alkylene, (C₂-C₆)-alkenylene, phenylene,        phenylene-(C₁-C₃)-alkyl, (C₁-C₃)-alkylenephenyl where the        bivalent (C₁-C₆)-alkylene radical can be unsubstituted or        substituted by a radical from the group consisting of        (C₁-C₈)-alkyl, (C₂-C₈)-alkenyl, (C₂-C₈)-alkynyl,        (C₃-C₁₀)-cycloalkyl, (C₃-C₁₀)-cycloalkyl-(C₁-C₆)-alkyl,        optionally substituted (C₆-C₁₄)-aryl,        (C₆-C₁₄)-aryl-(C₁-C₆)-alkyl optionally substituted in the aryl        radical, optionally substituted heteroaryl and        heteroaryl-(C₁-C₆)-alkyl optionally substituted in the        heteroaryl radical;    -   D is C(R²)(R³), N(R³) or CH═C(R³);    -   E is tetrazolyl, (R⁸O)₂P(O), HOS(O)₂, R⁹NHS(O)₂ or R¹⁰CO;    -   R is hydrogen, (C₁-C₈)-alkyl, (C₃-C₁₂)-cycloalkyl,        (C₃-C₁₂)-cycloalkyl-(C₁-C₈)-alkyl, optionally substituted        (C₆-C₁₄)-aryl, (C₆-C₁₄)-aryl-(C₁-C₈)-alkyl optionally        substituted in the aryl radical, optionally substituted        heteroaryl or heteroaryl-(C₁-C₈)-alkyl optionally substituted in        the heteroaryl radical, where alkyl radicals can be mono- or        polysubstituted by fluorine;    -   R⁰ is hydrogen, (C₁-C₈)-alkyl, (C₃-C₁₂)-cycloalkyl,        (C₃-C₁₂)-cycloalkyl-(C₁-C₈)-alkyl, (C₆-C₁₂)-bicycloalkyl,        (C₆-C₁₂)-bicycloalkyl-(C₁-C₈)-alkyl, (C₆-C₁₂)-tricycloalkyl,        (C₆-C₁₂)-tricycloalkyl-(C₁-C₈)-alkyl, optionally substituted        (C₆-C₁₄)-aryl, (C₆-C₁₄)-aryl-(C₁-C₈)-alkyl optionally        substituted in the aryl radical, optionally substituted        heteroaryl, heteroaryl-(C₁-C₈)-alkyl optionally substituted in        the heteroaryl radical, CHO, (C₁-C₈)-alkyl-CO,        (C₃-C₁₂)-cycloalkyl-CO, (C₃-C₁₂)-cycloalkyl-(C₁-C₈)-alkyl-CO,        (C₆-C₁₂)-bicycloalkyl-CO, C₆-C₁₂)-bicycloalkyl-(C₁-C₈)-alkyl-CO,        (C₆-C₁₂)-tricycloalkyl-CO,        (C₆-C₁₂)-tricycloalkyl-(C₁-C₈)-alkyl-CO, optionally substituted        (C₆-C₁₄)-aryl-CO, (C₆-C₁₄)-aryl-(C₁-C₈)-alkyl-CO optionally        substituted in the aryl radical, optionally substituted        heteroaryl-CO, heteroaryl-(C₁-C₈)-alkyl-CO optionally        substituted in the heteroaryl radical, (C₁-C₈)-alkyl-S(O)_(n),        (C₃-C₁₂)-cycloalkyl-S(O)_(n),        (C₃-C₁₂)-cycloalkyl-(C₁-C₈)-alkyl-S(O)_(n),        (C₆-C₁₂)-bicycloalkyl-S(O)_(n),        (C₆-C₁₂)-bicycloalkyl-(C₁-C₈)-alkyl-S(O)_(n),        (C₆-C₁₂)-tricycloalkyl-S(O)_(n),        (C₆-C₁₂)-tricycloalkyl-(C₁-C₈)-alkyl-S(O)_(n), optionally        substituted (C₆-C₁₄)-aryl-S(O)_(n),        (C₆-C₁₄)-aryl-(C₁-C₈)-alkyl-S(O)_(n) optionally substituted in        the aryl radical, optionally substituted heteroaryl-S(O)_(n) or        heteroaryl-(C₁-C₈)-alkyl-S(O)_(n) optionally substituted in the        heteroaryl radical, where n is 1 or 2;    -   R¹ is one of the radicals —S—R²¹, —S—S—R²¹, —S(O)—R²²,        —S(O)₂—R²², —S—OR²¹, —S(O)—OR²¹, —S(O)₂—OR²¹, —S—N(R²¹)—R²⁸,        —S(O)—N(R²¹)—R²⁸, —S(O)₂—N(R²¹)—R²⁸, —S—C(O)—R²¹, —S—C(O)—OR²²,        —S—C(S)—SR²², —S—C(O)—N(R²¹)—R²⁸, —S—C(S)—N(R²¹)—R²⁸,        —O—C(O)—R²¹, —O—C(S)—R²¹, —O—C(O)—OR²², —O—C(O)—N(R²¹)—R²⁸,        —O—C(S)—N(R²¹)—R²⁸, —O—S(O)₂—OR²¹, —O—S(O)—OR²¹,        —O—S(O)₂—N(R²¹)—R²⁸, —O—S(O)—N(R²¹)—R²⁸, —O—S(O)₂—R²²,        —O—S(O)—R²², —O—P(O)(OR²¹)₂, —O—P(O)(OR²¹)—N(R²¹)—R²⁸,        —O—P(O)(N(R²¹)—R²⁸)₂, —N(R²⁹)—C(O)—OR²², —N(R²⁸)—C(O)—SR²²,        —N(R²⁸)—C(S)—OR²², —N(R²⁸)—C(S)—SR²², —N(R²⁸)—C(S)—R²¹,        —N(R²⁸)—C(O)—N(R²¹)—R²⁸, —N(R²⁸)—C(S)—N(R²¹)—R²⁸,        —N(R²⁸)—S(O)₂—R²², —N(R²⁸)—S(O)—R²², —N(R²⁸)—S(O)₂—OR²¹,        —N(R²⁸)—S(O)—OR²¹, —N(R²⁸)—S(O)₂—N(R²¹)—R²⁸,        —N(R²⁸)—S(O)—N(R²¹)—R²⁸, —N(R²⁸)—P(O)(OR²¹)₂,        —N(R²⁸)—P(O)(OR²¹)—N(R²¹)—R²⁸, —N(R²⁸)—P(O)(N(R²¹)—R²⁸)₂,        —N(R²⁸)—P(O)(R²²)—OR²¹, —N(R²⁸)—P(O)(R²²)—N(R²¹)—R²⁸,        —N(R²⁸)—P(O)(R²²)₂, —P(O)(OR²¹)₂, —P(O)(OR²¹)—N(R²¹)—R²⁸,        —P(O)(N(R²¹)—R²⁸)₂, —P(O)(R²²)—OR²¹, —P(O)(R²²)—N(R²¹)—R²⁸,        —P(O)(R²²)₂, —C(S)—R²¹, —C(S)—SR²¹, —C(S)—N(R²¹)—R²⁸,

cyano, halogen, nitro or methylenedioxy or the radical of an optionallysubstituted, 5- to 14-membered, mono- or polycyclic, saturated orunsaturated heterocyclic ring of the formula

in which

Q¹ is —C(R²¹)₂—, ═C(R²¹)—, —N(R²⁸)—, —O— or —S—;

Q² is —S(O)— or —S(O)₂—;

Q³ is —C(R²¹)₂—, ═C(R₂₁)—, —N(R²⁸)—, —O—, —S—, —C(R²¹)(—)— or —N(—)—,

where the heterocyclic ring can be bonded to the group A via the freebond in the groups —C(R²¹)(—)— or —N(—)— representing Q³ or via anyother desired ring carbon atom and where, if the heterocyclic ring isbonded to a ring system contained in the group A, the heterocyclic ringcan also be fused via two adjacent atoms to the ring system in the groupA;

-   -   R² is hydrogen, (C₁-C₈)-alkyl, optionally substituted        (C₆-C₁₄)-aryl, (C₆-C₁₄)-aryl-(C₁-C₈)-alkyl optionally        substituted in the aryl radical or (C₃-C₈)-cycloalkyl;    -   R³ is hydrogen, (C₁-C₈)-alkyl, optionally substituted        (C₆-C₁₄)-aryl, (C₆-C₁₄)-aryl-(C₁-C₈)-alkyl optionally        substituted in the aryl radical, (C₃-C₈)-cycloalkyl,        (C₂-C₈)-alkenyl, (C₂-C₈)-alkynyl, (C₂-C₈)-alkenylcarbonyl,        (C₂-C₈)-alkynylcarbonyl, pyridyl, R¹¹NH, R⁴CO, COOR⁴,        CON(CH₃)R⁴, CONHR⁴, CSNHR⁴, COOR¹⁵, CON(CH₃)R¹⁵ or CONHR¹⁵;    -   R⁴ is hydrogen or (C₁-C₂₈)-alkyl which can optionally be mono-        or polysubstituted by identical or different radicals from the        group consisting of hydroxyl, hydroxycarbonyl, aminocarbonyl,        mono- or di-((C₁-C₁₈)-alkyl)aminocarbonyl,        amino-(C₂-C₁₈)-alkylaminocarbonyl,        amino-(C₁-C₃)-alkylphenyl-(C₁-C₃)-alkylaminocarbonyl,        (C₁-C₁₈)-alkylcarbonylamino-(C₁-C₃)-alkylphenyl-(C₁-C₃)-alkylaminocarbonyl,        (C₁-C₁₈)-alkylcarbonylamino-(C₂-C₁₈)-alkylaminocarbonyl,        (C₆-C₁₄)-aryl-(C₁-C₈)-alkoxycarbonyl which can also be        substituted in the aryl radical, ammo, mercapto,        (C₁-C₁₈)-alkoxy, (C₁-C₁₈)-alkoxycarbonyl, Het-CO, optionally        substituted (C₃-C₈)-cycloalkyl, HOS(O)₂—(C₁-C₃)-alkyl,        R⁹NHS(O)₂—(C₁-C₃)-alkyl, (R⁸O)₂P(O)—(C₁-C₃)-alkyl,        tetrazolyl-(C₁-C₃)-alkyl, halogen, nitro, trifluoromethyl or the        radical R⁵;    -   R⁵ is optionally substituted (C₆-C₁₄)-aryl,        (C₆-C₁₄)-aryl-(C₁-C₈)-alkyl optionally substituted in the aryl        radical, a mono- or bicyclic 5- to 12-membered heterocyclic ring        which can be aromatic, partially hydrogenated or completely        hydrogenated and which can contain one, two or three identical        or different heteroatoms from the group consisting of nitrogen,        oxygen and sulfur, a radical R⁶ or a radical R⁶CO—, where the        aryl radical and, independently thereof, the heterocyclic        radical can be mono- or polysubstituted by identical or        different radicals from the group consisting of (C₁-C₁₈)-alkyl,        (C₁-C₁₈)-alkoxy, halogen, nitro, amino and trifluoromethyl;    -   R⁶ is R⁷R⁸N, R⁷O or R⁷S or an amino acid side chain, a natural        or unnatural amino acid, imino acid, optionally        N—(C₁-C₈)-alkylated or N—(C₆-C₁₄)-aryl-(C₁-C₈)-alkylated)        azaamino acid or a dipeptide radical which can also be        substituted in the aryl radical and/or in which the peptide bond        can be reduced to —NH—CH₂—, and their esters and amides, where        hydrogen or hydroxymethyl can optionally stand in place of of        free functional groups and/or where free functional groups can        be protected by protective groups customary in peptide        chemistry;    -   R⁷ is hydrogen, (C₁-C₁₈)-alkyl, (C₆-C₁₄)-aryl-(C₁-C₈)-alkyl,        (C₁-C₁₈)-alkylcarbonyl, (C₁-C₁₈)-alkoxycarbonyl,        (C₆-C₁₄)-arylcarbonyl, (C₆-C₁₄)-aryl-(C₁-C₈)-alkylcarbonyl or        (C₆-C₁₄)-aryl-(C₁-C₁₈)-alkyloxycarbonyl, where the alkyl groups        can optionally be substituted by an amino group and/or where the        aryl radicals can be mono- or polysubstituted, preferably        monosubstituted, by identical or different radicals from the        group consisting of (C₁-C₈)-alkyl, (C₁-C₈)-alkoxy, halogen,        nitro, amino and trifluoromethyl, or is a natural or unnatural        amino acid, imino acid, optionally N—(C₁-C₈)-alkylated or        N—((C₆-C₁₄)-aryl-(C₁-C₈)-alkylated) azaamino acid or a dipeptide        radical which can also be substituted in the aryl radical and/or        in which the peptide bond can be reduced to —NH—CH₂—;    -   R⁸ is hydrogen, (C₁-C₁₈)-alkyl, optionally substituted        (C₆-C₁₄)-aryl or (C₆-C₁₄)-aryl-(C₁-C₈)-alkyl which can also be        substituted in the aryl radical;    -   R⁹ is hydrogen, aminocarbonyl, (C₁-C₁₈)-alkylaminocarbonyl,        (C₃-C₈)-cycloalkylaminocarbonyl, optionally substituted        (C₆-C₁₄)-arylaminocarbonyl, (C₁-C₁₈)-alkyl, optionally        substituted (C₆-C₁₄)-aryl or (C₃-C₈)-cycloalkyl;    -   R¹⁰ is hydroxyl, (C₁-C₁₈)-alkoxy, (C₆-C₁₄)-aryl-(C₁-C₈)-alkoxy        which can also be substituted in the aryl radical, optionally        substituted (C₆-C₁₄)-aryloxy, amino or mono- or        di-((C₁-C₁₈)-alkyl)amino;    -   R¹¹ is hydrogen, R^(12a), R^(12a)—CO, H—CO, R^(12a)—O—CO,        R^(12b)—CO, R^(12b)—CS, R^(12a)—S(O)₂ or R^(12b)—S(O)₂;    -   R^(12a) is (C₁-C₁₈)-alkyl, (C₂-C₈)-alkenyl, (C₂-C₈)-alkynyl,        (C₃-C₁₂)-cycloalkyl, (C₃-C₁₂)-cycloalkyl-(C₁-C₈)-alkyl,        optionally substituted (C₆-C₁₄)-aryl,        (C₆-C₁₄)-aryl-(C₁-C₈)-alkyl optionally substituted in the aryl        radical, optionally substituted heteroaryl,        heteroaryl-(C₁-C₈)-alkyl optionally substituted in the        heteroaryl radical or the radical R¹⁵;    -   R^(12b) is amino, di-((C₁-C₁₈)-alkyl)-amino or R^(12a)—NH;    -   R¹³ is hydrogen, (C₁-C₆)-alkyl, optionally substituted        (C₆-C₁₄)-aryl, (C₆-C₁₄)-aryl-(C₁-C₈)-alkyl optionally        substituted in the aryl radical, (C₃-C₈)-cycloalkyl or        (C₃-C₈)-cycloalkyl-(C₁-C₈)-alkyl;    -   R¹⁵ is R¹⁶—(C₁-C₆)-alkyl or R¹⁶;    -   R¹⁶ is a 6- to 24-membered, bicyclic or tricyclic radical which        is saturated or partially unsaturated and which can also contain        one, two, three or four identical or different heteroatoms from        the group consisting of nitrogen, oxygen and sulfur and which        can also be substituted by one or more identical or different        substituents from the group consisting of (C₁-C₄)-alkyl and oxo;    -   R²¹ is hydrogen, (C₁-C₈)-alkyl, hydroxy-(C₁-C₈)-alkyl,        (C₂-C₈)-alkenyl, (C₃-C₁₂)-cycloalkyl,        (C₃-C₁₂)-cycloalkyl-(C₁-C₈)-alkyl, optionally substituted        (C₆-C₁₄)-aryl, (C₆-C₁₄)-aryl-(C₁-C₈)-alkyl optionally        substituted in the aryl radical, optionally substituted        heteroaryl or heteroaryl-(C₁-C₈)-alkyl optionally substituted in        the heteroaryl radical, where alkyl radicals can also be        monosubstituted or polysubstituted by fluorine and the radicals        R²¹ can be identical or different if they occur two or more        times;    -   R²² is (C₁-C₈)-alkyl, hydroxy-(C₁-C₈)-alkyl, (C₂-C₈)-alkenyl,        (C₃-C₁₂)-cycloalkyl, (C₃-C₁₂)-cycloalkyl-(C₁-C₈)-alkyl,        optionally substituted (C₆-C₁₄)-aryl,        (C₆-C₁₄)-aryl-(C₁-C₈)-alkyl optionally substituted in the aryl        radical, optionally substituted heteroaryl or        heteroaryl-(C₁-C₈)-alkyl optionally substituted in the        heteroaryl radical, where alkyl radicals can be monosubstituted        or polysubstituted by fluorine and the radicals R²² can be        identical or different if they occur two or more times;    -   R²⁸ is one of the radicals R²¹—, R²¹N(R²¹)—, R²¹C(O)—,        R²²O—C(O)—, R²¹N(R²¹)—C(O)— or R²¹N(R²¹)—C(═N(R²¹))—;    -   R²⁹ is one of the radicals R²²—, R²¹N(R²¹)—, R²¹C(O)—,        R²²O—C(O)—, R²¹N(R²¹)—C(O)— or R²¹N(R²¹)—C(═N(R²¹))—;    -   Het is the radical of a 5- to 10-membered, monocyclic or        polycyclic heterocycle bonded via a nitrogen atom, which can be        aromatic or partially unsaturated or saturated and which can        contain one, two, three or four identical or different        additional ring heteroatoms from the group consisting of oxygen,        nitrogen and sulfur and which can be optionally substituted on        carbon atoms and on additional ring nitrogen atoms, where there        can be identical or different radicals R^(h), R^(h)CO or        R^(h)O—CO as substituents on additional ring nitrogen atoms and        R^(h) is hydrogen, (C₁-C₈)-alkyl, (C₃-C₈)-cycloalkyl,        (C₃-C₈)-cycloalkyl-(C₁-C₈)-alkyl, optionally substituted        (C₆-C₁₄)-aryl or (C₆-C₁₄)-aryl-(C₁-C₈)-alkyl optionally        substituted in the aryl radical;

b, c, d and f independently of one another can be 0 or 1, but cannot allsimultaneously be 0;

e, g and h independently of one another are the numbers 0, 1, 2, 3, 4, 5or 6;

in all their stereoisomeric forms and mixtures thereof in any ratio, andtheir physiologically tolerable salts.

All the above explanations for the compounds of the formula I, forexample with respect to alkyl radicals, aryl radicals, etc., apply tothe compounds of the formula Ib correspondingly. All the stereoisomersare also included here. Likewise, all the preferred meanings andpreferred compounds indicated above expressly also refer here to thecompounds of the formula Ib correspondingly. With respect to the use andthe pharmaceutical preparations, preferred compounds of the formula Ib,for example, are thus in turn those compounds in which

-   -   W is R¹-A-C(R¹³) or R¹-A-CH═C;    -   Y is a carbonyl, thiocarbonyl or methylene group;    -   Z is N(R⁰), oxygen, sulfur or a methylene group;    -   A is a bivalent radical from the group consisting of        (C₁-C₆)-alkylene, (C₃-C₁₂)-cycloalkylene,        (C₁-C₆)-alkylene-(C₃-C₁₂)-cycloalkyl, phenylene,        phenylene-(C₁-C₆)-alkyl, (C₁-C₆)-alkylenephenyl,        (C₁-C₆)-alkylenephenyl-(C₁-C₆)-alkyl, phenylene-(C₂-C₆)-alkenyl        or a bivalent radical of a 5- or 6-membered saturated or        unsaturated ring which can contain one or two nitrogen atoms and        can be mono- or disubstituted by (C₁-C₆)-alkyl or doubly bonded        oxygen or sulfur, or is a direct bond;    -   B is a bivalent radical from the group consisting of        (C₁-C₆)-alkylene, (C₂-C₆)-alkenylene, phenylene,        phenylene-(C₁-C₃)-alkyl, (C₁-C₃)-alkylenephenyl;    -   D is C(R²)(R³), N(R³) or CH═C(R³);    -   E is tetrazolyl, (R⁸O)₂P(O), HOS(O)₂, R⁹NHS(O)₂ or R¹⁰CO;    -   R and R⁰ independently of one another are hydrogen,        (C₁-C₈)-alkyl, (C₃-C₁₂)-cycloalkyl,        (C₃-C₁₂)-cycloalkyl-(C₁-C₈)-alkyl, optionally substituted        (C₆-C₁₄)-aryl, (C₆-C₁₄)-aryl-(C₁-C₈)alkyl optionally substituted        in the aryl radical, optionally substituted heteroaryl or        heteroaryl-(C₁-C₈)-alkyl optionally substituted in the        heteroaryl radical, where alkyl radicals can be mono- or        polysubstituted by fluorine;    -   R¹ is one of the radicals —S—R²¹, —S—S—R²¹, —S(O)—R²²,        —S(O)₂—R²², —S—OR²¹, —S(O)—OR²¹, —S(O)₂—OR²¹, —S—N(R²¹)—R²⁸,        —S(O)—N(R²¹)—R²⁸, —S(O)₂—N(R²¹)—R²⁸, —S—C(O)—R²¹, —S—C(O)—OR²²,        —S—C(S)—SR²², —S—C(O)—N(R²¹)—R²⁸, —S—C(S)—N(R²¹)—R²⁸,        —O—C(O)—R²¹, —O—C(S)—R²¹, —O—C(O)—OR²², —O—C(O)—N(R²¹)—R²⁸,        —O—C(S)—N(R²¹)—R²⁸, —O—S(O)₂—OR²¹, —O—S(O)—OR²¹,        —O—S(O)₂—N(R²¹)—R²⁸, —O—S(O)—N(R²¹)—R²⁸, —O—S(O)₂—R²²,        —O—S(O)—R²², —O—P(O)(OR²¹)₂, —O—P(O)(OR²¹)—N(R²¹)—R²⁸,        —O—P(O)(N(R²¹)—R²⁸)₂, —N(R²⁹)—C(O)—OR²², —N(R²⁸)—C(O)—SR²²,        —N(R²⁸)—C(S)—OR²², —N(R²⁸)—C(S)—SR²², —N(R²⁸)—C(S)—R²¹,        —N(R²⁸)—C(O)—N(R²¹)—R²⁸, —N(R²⁸)—C(S)—N(R²¹)—R²⁸,        —N(R²⁸)—S(O)₂—R²², —N(R²⁸)—S(O)—R²², —N(R²⁸)—S(O)₂—OR²¹,        —N(R²⁸)—S(O)—OR²¹, —N(R²⁸)—S(O)₂—N(R²¹)—R²⁸,        —N(R²⁸)—S(O)—N(R²¹)—R²⁸, —N(R²⁸)—P(O)(OR²¹)₂,        —N(R²⁸)—P(O)(OR²¹)—N(R²¹)—R²⁸, —N(R²⁸)—P(O)(N(R²¹)—R²⁸)₂,        —N(R²⁸)—P(O)(R²²)—OR²¹, —N(R²⁸)—P(O)(R²²)—N(R²¹)—R²⁸,        —N(R²⁸)—P(O)(R²²)₂, —P(O)(OR²¹)₂, —P(O)(OR²¹)—N(R²¹)—R²⁸,        —P(O)(N(R²¹)—R²⁸)₂, —P(O)(R²²)—OR²¹, —P(O)(R²²)—N(R²¹)—R²⁸,        —P(O)(R²²)₂, —C(S)—R²¹, —C(S)—SR²¹, —C(S)—N(R²¹)—R²⁸,

cyano, halogen, nitro or methylenedioxy or the radical of an optionallysubstituted, 5- to 14-membered, mono- or polycyclic, saturated orunsaturated heterocyclic ring of the formula

in which

Q¹ is —C(R²¹)₂—, ═C(R²¹)—, —N(R²⁸)—, —O— or —S—;

Q² is —S(O)— or —S(O)₂—;

Q³ is —C(R²¹)₂—, ═C(R²¹)—, —N(R²⁸)—, —O—, —S—, —C(R²¹)(—)— or —N(—)—,

where the heterocyclic ring can be bonded to the group A via the freebond in the groups —C(R²¹)(—)— or —N(—)— representing Q³ or via anyother desired ring carbon atom and where, if the heterocyclic ring isbonded to a ring system contained in the group A, the heterocyclic ringcan also be fused via two adjacent atoms to the ring system in the groupA;

-   -   R² is hydrogen, (C₁-C₈)-alkyl, optionally substituted        (C₆-C₁₄)-aryl, (C₆-C₁₄)-aryl-(C₁-C₈)-alkyl optionally        substituted in the aryl radical or (C₃-C₈ ₃)-cycloalkyl;    -   R³ is hydrogen, (C₁-C₈)-alkyl, optionally substituted        (C₆-C₁₄)-aryl, (C₆-C₁₄)-aryl-(C₁-C₈)-alkyl optionally        substituted in the aryl radical, (C₃-C₈)-cycloalkyl,        (C₂-C₈)-alkenyl, (C₂-C₈)-alkynyl, (C₂-C₈)-alkenylcarbonyl,        (C₂-C₈)-alkynylcarbonyl, pyridyl, R¹¹NH, R⁴CO, COOR⁴,        CON(CH₃)R⁴, CONHR⁴, CSNHR⁴, COOR¹⁵, CON(CH₃)R¹⁵ or CONHR¹⁵;    -   R⁴ is hydrogen or (C₁-C₂₈)-alkyl which can optionally be mono-        or polysubstituted by identical or different radicals from the        group consisting of hydroxyl, hydroxycarbonyl, aminocarbonyl,        mono- or di-((C₁-C₁₈)-alkyl)aminocarbonyl,        amino-(C₂-C₁₈)-alkylaminocarbonyl,        amino-(C₁-C₃)-alkylphenyl-(C₁-C₃)-alkylaminocarbonyl,        (C₁-C₁₈)-alkylcarbonylamino-(C₁-C₃)-alkylphenyl-(C₁-C₃)-alkylaminocarbonyl,        (C₁-C₁₈)-alkylcarbonylamino-(C₂-C₁₈)-alkylaminocarbonyl,        (C₆-C₁₄)-aryl-(C₁-C₈)-alkoxycarbonyl which can also be        substituted in the aryl radical, amino, mercapto,        (C₁-C₁₈)-alkoxy, (C₁-C₁₈)-alkoxycarbonyl, optionally substituted        (C₃-C₈)-cycloalkyl, HOS(O)₂-(C₁-C₃)-alkyl,        R⁹NHS(O)₂—(C₁-C₃)-alkyl, (R⁸O)₂P(O)—(C₁-C₃)-alkyl,        tetrazolyl-(C₁-C₃)-alkyl, halogen, nitro, trifluoromethyl and        the radical R⁵;    -   R⁵ is optionally substituted (C₆-C₁₄)-aryl,        (C₆-C₁₄)-aryl-(C₁-C₈)-alkyl optionally substituted in the aryl        radical, a mono- or bicyclic 5- to 12-membered heterocyclic ring        which can be aromatic, partially hydrogenated or completely        hydrogenated and which can contain one, two or three identical        or different heteroatoms from the group consisting of nitrogen,        oxygen and sulfur, a radical R⁶ or a radical R⁶CO—, where the        aryl radical and, independently thereof, the heterocyclic        radical can be mono- or polysubstituted by identical or        different radicals from the group consisting of (C₁-C₁₈)-alkyl,        (C₁-C₁₈)-alkoxy, halogen, nitro, amino or trifluoromethyl;    -   R⁶ is R⁷R⁸N, R⁷O or R⁷S or an amino acid side chain, a natural        or unnatural amino acid, imino acid, optionally        N—(C₁-C₈)-alkylated or N—((C₆-C₁₄)-aryl-(C₁-C₈)-alkylated)        azaamino acid or a dipeptide radical which can also be        substituted in the aryl radical and/or in which the peptide bond        can be reduced to —NH—CH₂—, and their esters and amides, where        hydrogen or hydroxymethyl can optionally stand in place of of        free functional groups and/or where free functional groups can        be protected by protective groups customary in peptide        chemistry;    -   R⁷ is hydrogen, (C₁-C₁₈)-alkyl, (C₆-C₁₄)-aryl-(C₁-C₈)-alkyl,        (C₁-C₁₈)-alkylcarbonyl, (C₁-C₁₈)-alkoxycarbonyl,        (C₆-C₁₄)-arylcarbonyl, (C₆-C₁₄)-aryl-(C₁-C₈)-alkylcarbonyl or        (C₆-C₁₄)-aryl-(C₁-C₁₈)-alkyloxycarbonyl, where the alkyl groups        can optionally be substituted by an amino group and/or where the        aryl radicals can be mono- or polysubstituted, preferably        monosubstituted, by identical or different radicals from the        group consisting of (C₁-C₈)-alkyl, (C₁-C₈)-alkoxy, halogen,        nitro, amino and trifluoromethyl, or is a natural or unnatural        amino acid, imino acid, optionally N—(C₁-C₈)-alkylated or        N—((C₆-C₁₄)-aryl-(C₁-C₈)-alkylated) azaamino acid or a dipeptide        radical which can also be substituted in the aryl radical and/or        in which the peptide bond can be reduced to —NH—CH₂—;    -   R⁸ is hydrogen, (C₁-C₁₈)-alkyl, optionally substituted        (C₆-C₁₄)-aryl or (C₆-C₁₄)-aryl-(C₁-C₈)-alkyl which can also be        substituted in the aryl radical;    -   R⁹ is hydrogen, aminocarbonyl, (C₁-C₁₈)-alkylaminocarbonyl,        (C₃-C₈)-cycloalkylaminocarbonyl, optionally substituted        (C₆-C₁₄)-arylaminocarbonyl, (C₁-C₁₈)-alkyl, optionally        substituted (C₆-C₁₄)-aryl or (C₃-C₈)-cycloalkyl;    -   R¹⁰ is hydroxyl, (C₁-C₁₈)-alkoxy, (C₆-C₁₄)-aryl-(C₁-C₈)-alkoxy        which can also be substituted in the aryl radical, optionally        substituted (C₆-C₁₄)-aryloxy, amino or mono- or        di-((C₁-C₁₈)-alkyl)amino;    -   R¹¹ is hydrogen, (C₁-C₁₈)-alkyl, R¹²CO, optionally substituted        (C₆-C₁₄)-aryl-S(O)₂, (C₁-C₁₈)-alkyl-S(O)₂,        (C₆-C₁₄)-aryl-(C₁-C₈)-alkyl optionally substituted in the aryl        radical, R⁹NHS(O)₂ or the radical R¹⁵;    -   R¹² is hydrogen, (C₁-C₁₈)-alkyl, (C₂-C₈)-alkenyl,        (C₂-C₈)-alkynyl, optionally substituted (C₆-C₁₄)-aryl,        (C₁-C₁₈)-alkoxy, (C₆-C₁₄)-aryl-(C₁-C₈)-alkoxy which can also be        substituted in the aryl radical, optionally substituted        (C₆-C₁₄)-aryloxy, amino or mono- or di-((C₁-C₁₈)-alkyl)amino,        the radical R¹⁵ or the radical R¹⁵—O—;    -   R¹³ is hydrogen, (C₁-C₆)-alkyl, (C₆-C₁₄)-aryl-(C₁-C₈)-alkyl        optionally substituted in the aryl radical or        (C₃-C₈)-cycloalkyl;    -   R¹⁵ is R¹⁶—(C₁-C₆)-alkyl or R¹⁶;    -   R¹⁶ is a 6- to 24-membered, bicyclic or tricyclic radical which        is saturated or partially unsaturated and which can also contain        one to four identical or different heteroatoms from the group        consisting of nitrogen, oxygen and sulfur and which can also be        substituted by one or more identical or different substituents        from the group consisting of (C₁-C₄)-alkyl and oxo;    -   R²¹ is hydrogen, (C₁-C₈)-alkyl, hydroxy-(C₁-C₈)-alkyl,        (C₂-C₈)-alkenyl, (C₃-C₁₂)-cycloalkyl,        (C₃-C₁₂)-cycloalkyl-(C₁-C₈)-alkyl, optionally substituted        (C₆-C₁₄)-aryl, (C₆-C₁₄)-aryl-(C₁-C₈)-alkyl optionally        substituted in the aryl radical, optionally substituted        heteroaryl or heteroaryl-(C₁-C₈)-alkyl optionally substituted in        the heteroaryl radical, where alkyl radicals can also be        monosubstituted or polysubstituted by fluorine and the radicals        R²¹ can be identical or different if they occur two or more        times;    -   R²² is (C₁-C₈)-alkyl, hydroxy-(C₁-C₈)-alkyl, (C₂-C₈)-alkenyl,        (C₃-C₁₂)-cycloalkyl, (C₃-C₁₂)-cycloalkyl-(C₁-C₈)-alkyl,        optionally substituted (C₆-C₁₄)-aryl,        (C₆-C₁₄)-aryl-(C₁-C₈)-alkyl optionally substituted in the aryl        radical, optionally substituted heteroaryl or        heteroaryl-(C₁-C₈)-alkyl optionally substituted in the        heteroaryl radical, where alkyl radicals can be monosubstituted        or polysubstituted by fluorine and the radicals R²² can be        identical or different if they occur two or more times;    -   R²⁸ is one of the radicals R²¹—, R²¹N(R²¹)—, R²¹C(O),        R²²O—C(O)—, R²¹N(R²¹)—C(O)— or R²¹N(R²¹)—C(═N(R²¹))—;    -   R²⁹ is one of the radicals R²²—, R²¹N(R²¹)—, R²¹C(O)—,        R²²O—C(O)—, R²¹N(R²¹)—C(O)— or R²¹N(R²¹)—C(═N(R²¹))—;

b, c, d and f independently of one another are 0 or 1, but cannot allsimultaneously be 0;

e, g and h independently of one another are 0, 1, 2, 3, 4, 5 or 6;

in all their stereoisomeric forms and mixtures thereof in any ratio, andtheir physiologically tolerable salts.

The compounds of the formula Ib according to the above definition havethe ability to inhibit the adhesion receptor VLA-4 and to inhibitcell-cell and cell-matrix interaction processes in which interactionsbetween VLA-4 and its ligands play a part. The activity of the compoundsof the formula Ib can be demonstrated, for example, in an assay in whichthe binding of cells which contain the VLA-4 receptor, for exampleleucocytes, to ligands of this receptor is measured, for example toVCAM-1, which for this purpose can advantageously also be prepared bygenetic engineering. Details of such an assay are described below. Inparticular, the compounds of the formula Ib are able to inhibit theadhesion and the migration of leucocytes, for example the adhesion ofleucocytes to endothelial cells which—as explained above—is controlledvia the VCAM-1/VLA-4 adhesion mechanism.

The compounds of the formula Ib and their physiologically tolerablesalts are therefore suitable for the treatment and prophylaxis ofdiseases which are based on the interaction between the VLA-4 receptorand its ligands or can be influenced by inhibition of this interaction,and in particular they are suitable for the treatment and prophylaxis ofdiseases which are caused at least partially by an undesired extent ofleucocyte adhesion and/or leucocyte migration or which are associatedtherewith, and for whose prevention, alleviation or cure the adhesionand/or migration of leucocytes should be reduced. They can thus beemployed, for example, as antinflammatory agents in the case ofinflammatory symptoms having very different causes. The compounds of theformula Ib according to the present invention are used, for example, forthe treatment or prophylaxis of rheumatoid arthritis, inflammatory boweldisease (ulcerative colitis), systemic lupus erythematosus or for thetreatment or prophylaxis of inflammatory disorders of the centralnervous system, such as, for example, multiple sclerosis, for thetreatment or prophylaxis of asthma or of allergies, for exampleallergies of the delayed type (type IV allergy), furthermore for thetreatment or prophylaxis of cardiovascular disorders, arteriosclerosis,restenosis, for the treatment or prophylaxis of diabetes, for theprevention of damage to organ transplants, for the inhibition of tumorgrowth or tumor metastasis in various malignancies, for the therapy ofmalaria, and also of other diseases in which blocking of the integrinVLA-4 and/or influencing of the leucocyte activity appears appropriatefor prevention, alleviation or cure. The compounds of the formula Ib andtheir salts can furthermore be employed for diagnostic purposes, e.g. inin vitro diagnoses, and as tools in biochemical investigations in whichVLA-4 blocking or influencing of cell-cell or cell-matrix interactionsis intended.

The compounds of the formula Ib and their physiologically tolerablesalts can be administered according to the invention, as pharmaceuticalsfor therapy or prophylaxis, to animals, preferably to mammals, and inparticular to man. They can be administered per se, in mixtures with oneanother or in the form of pharmaceutical preparations which permitenteral or parenteral use and which as active constituents contain anefficacious dose of at least one compound of the formula Ib and/or itsphysiologically tolerable salts in addition to customary,pharmaceutically innocuous excipients and/or additives. Thepharmaceutical preparations normally contain approximately 0.5 to 90% byweight of the therapeutically active compounds of the formula Ib and/ortheir physiologically tolerable salts.

The present invention relates to the compounds of the formula Ib and/ortheir physiologically tolerable salts for use as pharmaceuticals, theuse of the compounds of the formula Ib and/or their physiologicallytolerable salts for the production of pharmaceuticals for the inhibitionof the adhesion and/or migration of leucocytes or for the inhibition ofthe VLA-4 receptor, i.e. of pharmaceuticals for the treatment orprophylaxis of diseases in which leucocyte adhesion and/or leucocytemigration has an undesired extent, or of diseases in whichVLA-4-dependent adhesion processes play a part, in particular for theproduction of pharmaceuticals for the inhibition of inflammation, andalso the use of the compounds of the formula Ib and/or theirphysiologically tolerable salts in the treatment and prophylaxis ofdiseases of this type. The present invention furthermore relates topharmaceutical preparations which contain an efficacious dose of atleast one compound of the formula Ib and/or its physiologicallytolerable salts in addition to customary pharmaceutically innocuousexcipients and/or additives.

The pharmaceuticals can be administered orally, for example in the formof pills, tablets, film-coated tablets, sugar-coated tablets, granules,hard and soft gelatin capsules, solutions, syrups, emulsions orsuspensions. However, administration can also take place rectally, forexample in the form of suppositories, or parenterally, for example inthe form of injection or infusion solutions, microcapsules or rods, orpercutaneously, for example in the form of ointments or tinctures, or byother routes, for example in the form of nasal sprays or aerosolmixtures.

The pharmaceutical preparations to be employed according to theinvention are prepared in a manner known per se, pharmaceutically inertinorganic and/or organic excipients being used in addition to thecompound(s) of the formula Ib and/or its/their physiologically tolerablesalts. For the production of pills, tablets, sugarcoated tablets andhard gelatin capsules, it is possible to use, for example, lactose, cornstarch or derivatives thereof, talc, stearic acid or its salts, etc.Excipients for soft gelatin capsules and suppositories are, for example,fats, waxes, semisolid and liquid polyols, natural or hardened oils,etc. Suitable excipients for the preparation of solutions, for exampleinjection solutions, or of emulsions or syrups are, for example, water,alcohols, glycerol, polyols, sucrose, invert sugar, glucose, vegetableoils, etc. Suitable excipients for microcapsules, implants or rods are,for example, copolymers of glycolic acid and lactic acid.

In addition to the active compounds and excipients the pharmaceuticalpreparations can additionally contain additives, such as, for example,fillers, disintegrants, binders, lubricants, wetting agents,stabilizers, emulsifiers, preservatives, sweeteners, colorants,flavorings or aromatizers, thickeners, diluents, buffer substances, andalso solvents or solubilizers or agents for achieving a depot effect, aswell as salts for changing the osmotic pressure, coatings orantioxidants. They can also contain two or more compounds of the formulaIb and/or their physiologically tolerable salts. In addition to at leastone compound of the formula Ib and/or its physiologically tolerablesalts, they can further contain one or more other therapeutically orprophylactically active substances, for example substances havingantiinflammatory action.

The dose can vary within wide limits and is to be adapted to theindividual conditions in each individual case. In general, in the caseof oral administration a daily dose of approximately 0.01 to 100 mg/kg,preferably 0.1 to 10 mg/kg, in particular 0.3 to 2 mg/kg of body weightis adequate to achieve effective results. In the case of intravenousadministration, the daily dose is in general approximately 0.01 to 50mg/kg, preferably 0.01 to 10 mg/kg of body weight. The daily dose can besubdivided, in particular in the case of administration of relativelylarge amounts, into a number of, for example 2, 3 or 4, partadministrations. Where appropriate, it may be necessary, depending onindividual behavior, to deviate upwards or downwards from the indicateddaily dose. Pharmaceutical preparations normally contain 0.2 to 500 mg,preferably 1 to 100 mg, of active compound of the formula Ib and/or itsphysiologically tolerable salts per dose.

EXAMPLES

The products were identified by means of mass spectra (MS) and/or NMRspectra. Compounds which were purified by chromatography using an eluentwhich contained, for example, acetic acid or trifluoroacetic acid andwere then freeze-dried partly still contained, depending on thefreeze-drying procedure, the acid contained in the eluent, and were thuspartially or completely obtained in the form of a salt, for example inthe form of the acetic acid salt or trifluoroacetic acid salt.

The abbreviations have the following meanings:

-   -   THF Tetrahydrofuran    -   DMF N,N-Dimethylformamide    -   DCC N,N′-Dicyclohexylcarbodiimide    -   HOBt 1-Hydroxybenzotriazole

Example 1((R,S)-4-(4-(Cyanophenyl)-4-methyl-3-(2-naphthylmethyl)-2,5-dioxoimidazolidin-1-yl)acetyl-L-aspartyl-L-phenylglycine

1a) (R,S)-4-(4-Cyanophenyl)-4-methyl-2,5-dioxoimidazolidine

20 g (138 mmol) of p-acetylbenzonitrile, 115.6 g of ammonium carbonate(1.21 mol) and 11.6 g of potassium cyanide (178 mmol) were dissolved in600 ml of a mixture of 50% ethanol and 50% water. The mixture wasstirred at 55° C. for 5 hours and allowed to stand at room temperatureovernight. The solution was adjusted to pH=6.3 using 6 N HCl and thenstirred at room temperature for 2 hours. The precipitate was filteredoff with suction, washed with water and dried over phosphorus pentoxidein a high vacuum. Yield: 22.33 g (75%).

FAB-MS: 216.1 (M+H)⁺

1b) Methyl((R,S)-4-(4-cyanophenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetate

1.068 g of sodium (46.47 mmol) were dissolved in 110 ml of abs. methanolunder nitrogen. The clear solution was treated with 10 g of(R,S)-4-(4-cyanophenyl)-4-methyl-2,5-dioxoimidazolidine (46.47 mmol) andthe mixture was boiled under reflux for 2 h. 7.75 g (46.68 mmol) ofpotassium iodide were added and a solution of 4.53 ml of methylchloroacetate (51.3 mmol) in 5 ml of methanol was added dropwise in thecourse of 1 hour. The mixture was heated to boiling for 6 hours, allowedto stand at room temperature overnight and concentrated. The oilyresidue was chromatographed on silica gel using methylene chloride/ethylacetate (9:1). Yield: 8.81 g (66%).

FAB-MS: 288 (M+H)⁺

1c) Methyl((R,S)4-(4-cyanophenyl)4-methyl-3-(2-naphthylmethyl-2,5-dioxoimidazolidin-1-yl)acetate

5 g of methyl((R,S)-4-(4-cyanophenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetate(17.4 mmol) were dissolved in 20 ml of anhydrous DMF under argon. 920 mgof a sodium hydride dispersion in mineral oil (19.14 mmol) were added inan argon countercurrent. The reaction mixture was stirred at roomtemperature for 15 minutes. A solution of 3.85 g of2-bromomethylnaphthalene (19.14 mmol) in 10 ml of anhydrous DMF was thenadded. The mixture was stirred at room temperature for 4 hours and thenallowed to stand at room temperature overnight. The solution wasconcentrated. For purification, the substance was chromatographed onsilica gel using methylene chloride/ethyl acetate (9.75:0.25). Thefractions containing the pure substance were concentrated. Yield: 5.15 gof oil (69%).

FAB-MS: 428.3 (M+H)⁺

1d)((R,S)-4-(4-cyanophenyl)-4-methyl-3-(2-naphthylmethyl)-2,5-dioxoimidazoldin-1-yl)aceticacid

1.1 g of methyl((R,S)-4-(4-cyanophenyl)-4-methyl-3-(2-naphthylmethyl)-2,5-dioxoimidazolidin-1-yl)acetate(2.57 mmol) were dissolved in a mixture of 20 ml of 6 N HCl and 10 ml ofdioxane. The solution was stirred at 70° C. for 3 hours and thenconcentrated.

Yield: 1.2 g of crude product. FAB-MS: 414.2 (M+H)⁺

1e)((R,S)-4-(4-cyanophenyl)-4-methyl-3-(2-naphthylmethyl)-2,5-dioxoimidazolidin1-yl)acetyl-L-aspartyl-L-phenylglycine di-tert-butyl ester

515 mg of DCC (2.34 mmol) were added at 0° C. to a solution of 1.2 g of((R,S)-4-(4-Cyanophenyl)-4-methyl-3-(2-naphthylmethyl)-2,5-dioxoimidazolidin-1-yl)aceticacid (crude product), 0.97 g of H-Asp(OBu^(t)-Phg-OBu^(t) hydrochloride(2.34 mmol) and 320 mg of HOBt (2.34 mmol) in 25 ml of DMF. The mixturewas stirred at 0° C. for 1 hour and at room temperature for 3 hours. Thebatch was then allowed to stand at room temperature overnight, theprecipitate was filtered off with suction and the filtrate wasconcentrated. For purification, the substance was chromatographed onsilica gel, first with methylene chloride/methanol/glacial acetic acid(9.5:0.5:0.05) and then with methylene chloride/ethyl acetate (8:2).Yield: 620 mg of an oil (34.4%).

FAB-MS: 774.3 (M+H)⁺

1f)((R,S)-4-(4-cyanophenyl)-4-methyl-3-(2-naphthylmethyl)-2,5-dioxoimidazolidin-1-yl)acetyl-L-aspartyl-L-phenylglycine

250 mg of((R,S)-4-(4-cyanophenyl)-4-methyl-3-(2-naphthylmethyl)-2,5dioxoimidazolidin-1-yl)acetyl-L-aspartyl-L-phenylglycinedi-tert-butyl ester were dissolved in a mixture of 2.25 ml oftrifluoroacetic acid and 0.25 ml of water. The mixture was allowed tostand at room temperature for one hour and was concentrated in awater-jet vacuum. For purification, the substance was chromatographed onSephadex LH20 using a mixture of glacial acetic acid, n-butanol andwater. The fractions containing the pure substance were concentrated.The residue was dissolved in water, freeze-dried and, for furtherpurification, chromatographed on silica gel using methylenechloride/methanol/glacial acetic acid/water (9:1:0.01:0.1).

Yield: 78 mg (36.8%). FAB-MS: 662.2 (M+H)⁺

Example 2 ((R,S)-3-Benzyl-4-methyl-4-(4-nitrophenyl)-2,5-dioxoimidazolidin-1-yl)acetyl-L-aspartyl-L-phenylglycine

2a) (R,S)-4-Methyl-4-(4-nitrophenyl)-2,5-dioxoimidazolidine

A mixture of 20 g (121 mmol) of 4-nitroacetophenone, 101.65 g (1.06 mol)of ammonium carbonate and 10.2 g (156 mmol) of potassium cyanide in 400ml of ethanol/water (1:1) was heated at 50° C. for 5 h. The solution wasthen adjusted to pH=6.3 using 6 N hydrochloric acid and stirred at roomtemperature for 2 h. The precipitate was filtered off with suction,washed with water and dried over phosphorus pentoxide in a high vacuum.Yield: 27.37 g (96%) of colorless solid.

2b)((R,S)-3-Benzyl-4-methyl-4-(4-nitrophenyl)-2,5-dioxoimidazolidin-1-yl)aceticacid

The compound was prepared analogously to Example 1 by reaction of(R,S)-4-methyl-4-(4-nitrophenyl)-2,5-dioxoimidazolidine with methylbromoacetate and then benzyl bromide (instead of2-bromomethylnaphthalene) and cleavage of the methyl ester with 6 Nhydrochloric acid.

2c)((R,S)-3-Benzyl-4-methyl-4-(4-nitrophenyl)-2,5-dioxoimidazolidin-l-yl)acetyl-L-aspartyl-L-phenylglycine

A solution of 383 mg (1 mmol) of((R,S)-3-benzyl-4-methyl-4-(4-nitrophenyl)-2,5-dioxoimidazolidin-l-yl)aceticacid, 414 mg (1 mmol) of H-Asp(O^(t)Bu)-Phg-(O^(t)Bu)×HCl and 135 mg (1mmol) of HOBt in 5 ml of absolute DMF was treated at 0° C. with 220 mg(1.1 mmol) of DCC. After stirring at 0° C. for 60 minutes and at roomtemperature for 60 minutes, the precipitate was filtered off withsuction, the filtrate was concentrated and the residue was taken up inethyl acetate. After filtration, the ethyl acetate solution was washedin succession with saturated NaHCO₃ solution, KHSO₄/K₂SO₄ solution,saturated NaHCO₃ solution and water. After phase separation, the organicphase was dried over sodium sulfate. The drying agent was filtered off,the solvent was removed in vacuo and the residue was chromatographed onsilica gel using dichloromethane/ethyl acetate (9:1). Afterconcentration of the product fractions, the residue was treated with 10ml of 90% strength trifluoroacetic acid. After 1 h at room temperature,the trifluoroacetic acid was removed in vacuo and the residue waschromatographed on silica gel using dichloromethane/methanol/glacialacetic acid/water (9:1:0.1:0.1) and then on Sephadex LH20 usingwater/butanol/acetic acid (43:4.3:3.5). After freeze-drying of theproduct fractions, 23 mg (4%) of the title compound were obtained.

ES(+)-MS: 632 (M+H)⁺

Example 3 ((R,S)-3-Benzyl-4-methyl-4-(4-(3-(2-methylphenyl)ureido)phenyl)-2,5-dioxoimidazolidin-1-yl)acetyl-L-aspartyl-L-phenylglycine

3a) Methyl((R,S)-3-benzyl-4-methyl-4-(4-nitrophenyl)-2,5-dioxoimidazolidin-1-yl)acetate

The compound was prepared from(R,S)-4-methyl-(4-nitrophenyl)-2,5-dioxoimidazolidine (synthesized from4-nitroacetophenone as described in Example 2) analogously to Example 1.

3b) Methyl((R,S)-4-(4-aminophenyl)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)acetate

A solution of 8.92 g (22.45 mmol) of methyl((R,S)-3-benzyl-4-methyl-4-(4-nitrophenyl)-2,5-dioxoimidazolidin-1-yl)acetatein 280 ml of absolute methanol was treated with 17 g (90 mmol) of tinchloride and 3 drops of acetic acid and heated at 50° C. After startingmaterial was no longer detectable according to HPLC checking, thereaction mixture was concentrated in vacuo and the residue was filteredthrough silica gel using methanol. After concentration, 6.39 g (78%) ofthe title compound were obtained.

3c) Methyl((R,S)-3-benzyl-4-methyl-4-(4-(3-(2-methylphenyl)ureido)-phenyl)-2,5-dioxoimidazolidin-1-yl)acetate

0.91 g (6.8 mmol) of ortho-tolyl isocyanate in 2 ml of THF was added toa solution of 2.5 g (6.8 mmol) of methyl((R,S)-4-(4-aminophenyl)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)acetatein 20 ml of THF. After heating under reflux for 5 h, the reactionmixture was allowed to stand at room temperature overnight, a further0.18 g (1.36 mmol) of ortho-tolyl isocyanate was added and it wasstirred under reflux for 3 h. The reaction mixture was concentrated andthe residue was purified on silica gel by means of MPLC usingheptane/ethyl acetate (1:1). After concentration of the productfractions, 1.35 g (40%) of the title compound were obtained.

3d)((R,S)-3-Benzyl-4-methyl-4-(4-(3-(2-methylphenyl)ureido)phenyl)-2,5-dioxoimidazolidin-1-yl)acetyl-L-aspartyl-L-phenylglycine

The synthesis was carried out analogously to Example 2 by coupling of((R,S)-3-benzyl-4-methyl-4-(4-(3-(2-methylphenyl)ureido)phenyl)-2,5-dioxoimidazolidin-1-yl)aceticacid (prepared by cleavage of methyl((R,S)-3-benzyl-4-methyl-4-(4-(3-(2-methylphenyl)ureido)phenyl)-2,5-dioxoimidazolidin-1-yl)acetatewith 6 N hydrochloric acid analogously to Example 1) andH-Asp(O^(t)Bu)-Phg-(O^(t)Bu)×HCl. After cleavage of the tert-butyl esterwith 90% strength trifluoroacetic acid, the crude product was purifiedby preparative HPLC on RP-18.

ES(+)-MS: 735 (M+H)⁺

Example 4((R,S)-3-Benzyl-4-(4-(3-benzylureidomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetyl-L-aspartyl-L-phenylglycine

4a) Methyl((R,S)-3-benzyl-4-(4-cyanophenyl)4-methyl-2,5-dioxoimidazolidin-1-yl)acetate

28.7 g (100 mmol) of methyl((R,S)-4-(4-cyanophenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetatewere dissolved in 160 ml of anhydrous DMF under argon. 5.28 g (110 mmol)of NaH were added in portions with stirring at 0° C. The mixture wasstirred at 0° C. for 30 minutes. 13 ml of benzyl bromide were thenslowly added dropwise. The mixture was stirred at room temperature for 5hours and allowed to stand at room temperature overnight. The almostclear solution was filtered with suction and concentrated in a highvacuum. The residue was dissolved in ethyl acetate, the solution waswashed with water and the aqueous phase was washed with ethyl acetate.The combined organic phases were washed with water, dried with anhydrousmagnesium sulfate and concentrated. For purification, the crude productwas chromatographed on silica gel (70-200 μm) in n-heptane/ethyl acetate(1:1). 35.7 g (94.6%) of the title compound were obtained as an oil.

4b) Methyl((R,S)-4-(4-(aminomethyl)phenyl)-3-benzyl-4-methyl-2,5-dioxo-imidazolidin-1-yl)acetate

15.2 g (40 mmol) of methyl((R,S)-3-benzyl-4-(4-cyanophenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetate(4a) were dissolved in 160 ml of a mixture of ethanol and 50% strengthacetic acid (8:2), treated with 3 g of Pd/carbon and hydrogenated for 7hours in an autoclave at 3 bar of H₂. The catalyst was filtered off withsuction and the filtrate was concentrated. The residue was dissolved indichloromethane and chromatographed on silica gel (70-200 μm) usingdichloromethane and then dichloromethane/methanol (8:2). 15.3 g (100%)of the title compound were obtained.

4c) Methyl((R,S)-3-benzyl-4-(4-(3-benzylureidomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetate

3.80 g (10 mmol) of methyl((R,S)-4-4-(aminomethyl)phenyl)-3-benzyl-4-methyl-2,5-dioxoimidazolidin-1-yl)acetate(4b) were dissolved in 20 ml of anhydrous dichloromethane under argon.1.85 ml (2 g; 15 mmol) of benzyl isocyanate and 2 drops of triethylaminewere added. The mixture was stirred at room temperature for 2 hours andthe solution was concentrated a little. It was diluted with ethylacetate and washed 2× with 5% strength citric acid, 2× with saturatedNaHCO₃ solution and 1× with water/NaCl solution. The solution was driedover anhydrous sodium sulfate and concentrated. 5.09 g (98.9%) of thetitle compound were obtained as an oil.

4d)((RS)-3-Benzyl-4-(4-(3-benzylureidomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)aceticacid

1 g (1.94 mmol) of methyl((R,S)-3-benzyl-4-(4-(3-benzylureidomethyl)-phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetate(4c) were refluxed for 5 hours with 20 ml of concentrated hydrochloricacid. The mixture was then concentrated. The residue was triturated withwater, cooled and filtered off with suction. 700 mg (72%) of the titlecompound were obtained.

4e)((R,S)-3-Benzyl-4-(4-(3-benzylureidomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetyl-L-aspartyl-L-phenylglycinedi-tert-butyl ester

500 mg (1 mmol) of((R,S)-3-benzyl-4-(4-(3-benzylureidomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)aceticacid (4d), 414.9 mg (1 mmol) of H-Asp(O^(t)Bu)-Phg-(O^(t)Bu)×HCl and 135mg (1 mmol) of HOBt were dissolved in 10 ml of absolute DMF. 413 ml (1mmol) of N-ethylmorpholine and 220 mg (1.1 mmol) of DCC were added at 0°C. The mixture was stirred at 0° C. for 1 hour and at room temperaturefor 3 hours. It was allowed to stand at room temperature overnight, theurea precipitate was filtered off with suction and the filtrate wasconcentrated in a high vacuum. The residue was taken up in ethylacetate, and washed with saturated NaHCO₃ solution, KHSO₄/K₂SO₄ solutionand with water/NaCl solution. The organic phase was dried with anhydroussodium sulfate and concentrated, and the oily residue was dried in ahigh vacuum. 800 mg (92.9%) of the title compound were obtained.

4f)((R,S)-3-Benzyl-4-(4-(3-benzylureidomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetyl-L-aspartyl-L-phenylglycine

800 mg (0.93 mmol) of((R,S)-3-benzyl-4-(4-(3-benzylureidomethyl)phenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetyl-L-aspartyl-L-phenylglycinedi-tert-butyl ester (4e) were dissolved in 8 ml of 90% strengthtrifluoroacetic acid and allowed to stand at room temperature for 1hour. The mixture was then concentrated and the residue was trituratedwith diethyl ether. The crude product was purified by chromatography onsilica gel using dichloromethane/methanol/acetic acid/water(9:1:0.1:0.1). 527 mg (76%) of the title compound were obtained.

ES(+)-MS: 749.3 (M+H)⁺

Example 5((RS)-3-Benzyl-4-methyl-4-(4-(3-phenylureidomethyl)phenyl)-2,5-dioxoimidazolidin-1-yl)acetyl-L-aspartyl-L-phenylglycine

The synthesis was carried out analogously to Example 4. After cleavageof the tert-butyl ester using 90% strength trifluoroacetic acid, thecrude product was purified by chromatography on silica gel usingdichloromethane/methanol/acetic acid/water (9:1:0.1:0.1).

ES(+)-MS: 735.2 (M+H)⁺

Example 6 ((R,S)-3-Benzyl-4-methyl-4-(4-(3-(2-methylphenyl)ureidomethyl)phenyl)-2,5-dioxoimidazolidin-1-yl)acetyl-L-aspartyl-L-phenylglycine

The synthesis was carried out analogously to Example 4. After cleavageof the tert-butyl ester using 90% strength trifluoroacetic acid, thecrude product was purified by chromatography on silica gel usingdichloromethane/methanol/acetic acid/water (9:1:0.1:0.1).

ES(+)-MS: 749.3 (M+H)⁺

Example 7((R,S)-3-Benzyl-4-methyl-4-(4-(3-(2-phenylethyl)ureidomethyl)phenyl)-2,5-dioxoimidazolidin-1-yl)acetyl-L-aspartyl-L-phenylglycine

The synthesis was carried out analogously to Example 4. After cleavageof the tert-butyl ester using 90% strength trifluoroacetic acid, thecrude product was purified by chromatography on silica gel usingdichloromethane/methanol/acetic acid/water (9:1:0.1:0.1).

ES(+)-MS: 763.3 (M+H)⁺

Investigation of the biological activity

As a test method for the activity of the compounds of the formula Ib onthe interaction between VCAM-1 and VLA-4, an assay is used which isspecific for this interaction. The cellular binding components, i.e. theVLA-4-integrins, are offered in their natural form as surface moleculeson human U937 cells (ATCC CRL 1593), which belong to the group ofleucocytes. As specific binding components, recombinant soluble fusionproteins prepared by genetic engineering and consisting of theextracytoplasmic domains of human VCAM-1 and the constant region of ahuman immunoglobulin of the subclass IgG1 are used.

Test method

Assay for the measurement of the adhesion of U937 cells (ATCC CRL 1593)to hVCAM-1(1-3)-IgG

1. Preparation of human VCAM-1(1-3)-IgG and human CD4-IgG

A genetic construct for the expression of the extracellular domains ofhuman VCAM-1 was employed, associated with the genetic sequence of theheavy chain of human immunoglobulin IgG-1 (hinge, CH2 and CH3 regions),from Dr. Brian Seed, Massachusetts General Hospital, Boston, USA. Thesoluble fusion protein hVCAM-1(1-3)-IgG contained the threeamino-terminal extracellular immunoglobulin-like domains of human VCAM-1(Damle and Aruffo, Proc. Natl. Acad. Sci. USA 1991, 88, 6403). CD4-IgG(Zettlmeissl et al., DNA and Cell Biology 1990, 9, 347) served as afusion protein for negative controls. The recombinant proteins wereexpressed as soluble proteins after DEAE/dextran-mediatedDNA-transfection in COS cells (ATCC CRL1651) according to standardprocedures (Ausubel et al., Current protocols in molecular biology, JohnWiley & Sons, Inc., 1994).

2. Assay for measurement of the adhesion of U937 cells tohVCAM-1(1-3)-IgG

2.1 96-well microtiter test plates (Nunc Maxisorb) were incubated atroom temperature for 1 hour with 100 μl/well of a goat-anti-human IgGantibody solution (10 μg/ml in 50 mM Tris, pH 9.5). After removing theantibody solution, washing was carried out once with PBS.

2.2 150 μl/well of a blocking buffer (1% BSA in PBS) was incubated onthe plates at room temperature for 0.5 hours. After removing theblocking buffer, washing was carried out once with PBS.

2.3 100 μl per well of a cell culture supernatant of transfected COScells were incubated on the plates at room temperature for 1.5 hours.The COS cells were transfected with a plasmid which codes for the threeN-terminal immunoglobulin-like domains of VCAM-1, coupled to the Fc partof human IgG₁ (hVCAM-1(1-3)-IgG). The content of hVCAM-1(1-3)-IgG wasabout 0.5-1 μg/ml. After removing the culture supernatant, washing wascarried out once with PBS.

2.4 The plates were incubated at room temperature for 20 minutes with100 μl/well of Fc receptor blocking buffer (1 mg/ml of γ-globulin, 100mM NaCl, 100 μM MgCl₂, 100 μM MnCl₂, 100 μM CaCl₂, 1 mg/ml BSA in 50 mMHEPES, pH 7.5). After removing the Fc receptor blocking buffer, washingwas carried out once with PBS.

2.5 20 μl of binding buffer (100 μM NaCl, 100 μM MgCl₂, 100 μM MnCl₂,100 μM CaCl₂, 1 mg/ml BSA in 50 mM HEPES, pH 7.5), were initiallyintroduced, the substances to be tested were added in 10 μl of bindingbuffer and the mixture was incubated for 20 minutes. As controls,antibodies against VCAM-1 (BBT, No. BBA6) and against VLA-4 (Immunotech,No. 0764) were used.

2.6 U937 cells were incubated in Fc receptor blocking buffer for 20minutes and then pipetted in at a concentration of 1×10⁶/ml and in anamount of 100 μl per well (final volume 125 μl/well).

2.7 The plates were slowly immersed at an angle of 45° in stop buffer(100 mM NaCl, 100 μM MgCl₂, 100 μM MnCl₂, 100 μM CaCl₂ in 25 mM Tris, pH7.5) and shaken off. The process was repeated.

2.8 50 μl/well of a dye solution (16.7 μg/ml of Hoechst dye 33258, 4%formaldehyde, 0.5% Triton X-100 in PBS) were then incubated on theplates for 15 minutes.

2.9 The plates were shaken off and slowly immersed at an angle of 45° instop buffer (100 mM NaCl, 100 μM MgCl₂, 100 μM MnCl₂, 100 μM CaCl₂ in 25mM tris, pH 7.5). The process was repeated. Then, with the liquid,measurements were made in a cytofluorimeter (Millipore) (sensitivity: 5;filter: excitation wavelength: 360 nm, emission wavelength: 460 nm).

The intensity of the light emitted by the stained U937 cells is ameasure of the number of the U937 cells adhered to the hVCAM-1(1-3)-IgGand remaining on the plate and thus a measure of the ability of theadded test substance to inhibit this adhesion. From the inhibition ofthe adhesion at various concentrations of the test substance, theconcentration IC₅₀ which leads to an inhibition of adhesion by 50% wascalculated.

The following test results were obtained:

U937/VCAM-1 cell adhesion test Example IC₅₀ (μM) 1 30 2 27.7 3 2.8 4 145 9 6 6.5 7 20

It will be apparent to those skilled in the art that variousmodifications and variations can be made to the compounds, compositions,kits, and processes of this invention. Thus, it is intended that thepresent invention cover such modifications and variations, provided theycome within the scope of the appended claims and their equivalents.

The disclosure of all publications cited above are expresslyincorporated herein by reference in their entireties to the same extentas if each were incorporated by reference individually. The disclosureof German Patent Application No. 19647381.0, for which benefit under 35USC § 119 is claimed, is expressly incorporated herein in its entirety.

1. A compound of the formula I

in which W is R¹-A-C(R¹³); Y is a carbonyl, thiocarbonyl or methylenegroup; Z is N(R⁰), oxygen, sulfur or a methylene group; A is a bivalentradical from the group consisting of (C₁-C₆)-alkylene,(C₃-C₁₂)-cycloalkylene, (C₁-C₆)-alkylene-(C₃-C₁₂)-cycloalkyl, phenylene,phenylene-(C₁-C₆)-alkyl, (C₁-C₆)-alkylenephenyl,(C₁-C₆)-alkylenephenyl-(C₁-C₆)-alkyl, phenylene-(C₂-C₆)-alkenyl or abivalent radical of a 5- or 6-membered saturated or unsaturated ringwhich can contain 1 or 2 nitrogen atoms and can be mono- ordisubstituted by (C₁-C₆)-alkyl or doubly bonded oxygen or sulfur, or isa direct bond; B is a bivalent radical from the group consisting of(C₁-C₆)-alkylene, (C₂-C₆)-alkenylene, phenylene,phenylene-(C₁-C₃)-alkyl, (C₁-C₃)-alkylenephenyl, where the bivalent(C₁-C₆)-alkylene radical can be unsubstituted or substituted by aradical from the group consisting of (C₁-C₈)-alkyl, (C₂-C₈)-alkenyl,(C₂-C₈)-alkynyl, (C₃-C₁₀)-cycloalkyl, (C₃-C₁₀)-cycloalkyl-(C₁-C₆)-alkyl,optionally substituted (C₆-C₁₄)-aryl, (C₆-C₁₄)-aryl-(C₁-C₆)-alkyloptionally substituted in the aryl radical, optionally substitutedheteroaryl and heteroaryl-(C₁-C₆)-alkyl optionally substituted in theheteroaryl radical; D is C(R²)(R³); E is tetrazolyl, (R⁸O)₂P(O),HOS(O)₂, R⁹NHS(O)₂ or R¹⁰ CO; R is hydrogen, (C₁-C₈)-alkyl,(C₃-C₁₂)-cycloalkyl, (C₃-C₁₂)-cycloalkyl-(C₁-C₈)-alkyl, optionallysubstituted (C₆-C₁₄)-aryl, (C₆-C₁₄)-aryl-(C₁-C₈)-alkyl optionallysubstituted in the aryl radical, optionally substituted heteroaryl andheteroaryl-(C₁-C₈)-alkyl optionally substituted in the heteroarylradical, where alkyl radicals can be mono- or polysubstituted byfluorine; R⁰ is hydrogen, (C₁-C₈)-alkyl, (C₃-C₁₂)-cycloalkyl,(C₃-C₁₂)-cycloalkyl-(C₁-C₈)-alkyl, (C₆-C₁₂)-bicycloalkyl,(C₆-C₁₂)-bicycloalkyl-(C₁-C₈)-alkyl, (C₆-C₁₂)-tricycloalkyl,(C₆-C₁₂)-tricycloalkyl-(C₁-C₈)-alkyl, optionally substituted(C₆-C₁₄)-aryl, (C₆-C₁₄)-aryl-(C₁-C₈)-alkyl optionally substituted in thearyl radical, optionally substituted heteroaryl,heteroaryl-(C₁-C₈)-alkyl optionally substituted in the heteroarylradical, CHO, (C₁-C₈)-alkyl-CO, (C₃-C₁₂)-cycloalkyl-CO,(C₃-C₁₂)-cycloalkyl-(C₁-C₈)-alkyl-CO, (C₆-C₁₂)-bicycloalkyl-CO,(C₆-C₁₂)-bicycloalkyl-(C₁-C₈)-alkyl-CO, (C₆-C₁₂)-tricycloalkyl-CO,(C₆-C₁₂)-tricycloalkyl-(C₁-C₈)-alkyl-CO, optionally substituted(C₆-C₁₄)-aryl-CO, (C₆-C₁₄)-aryl-(C₁-C₈)-alkyl-CO optionally substitutedin the aryl radical, optionally substituted heteroaryl-CO,heteroaryl-(C₁-C₈)-alkyl-CO optionally substituted in the heteroarylradical, (C₁-C₈)-alkyl-S(O)_(n), (C₃-C₁₂)-cycloalkyl-S(O)_(n),(C₃-C₁₂)-cycloalkyl-(C₁-C₈)-alkyl-S(O)_(n),(C₆-C₁₂)-bicycloalkyl-S(O)_(n),(C₆-C₁₂)-bicycloalkyl-(C₁-C₈)-alkyl-S(O)_(n),(C₆-C₁₂)-tricycloalkyl-S(O)_(n),(C₆-C₁₂)-tricycloalkyl-(C₁-C₈)-alkyl-S(O)_(n), optionally substituted(C₆-C₁₄)-aryl-S(O)_(n), (C₆-C₁₄)-aryl-(C₁-C₈)-alkyl-S(O)_(n) optionallysubstituted in the aryl radical, optionally substitutedheteroaryl-S(O)_(n) or heteroaryl-(C₁-C₈)-alkyl-S(O)_(n) optionallysubstituted in the heteroaryl radical, where n is 1 or 2; R¹ is one ofthe radicals —S—R²¹, —S—S—R²¹, —S(O)—R²², —S(O)₂—R²², —S—OR²¹,—S(O)—OR²¹, —S(O)₂—OR²¹, —S—N(R²¹)—R²⁸, —S(O)—N(R²¹)—R²⁸,—S(O)₂—N(R²¹)—R²⁸, —S—C(O)—R²¹, —S—C(O)—OR²², —S—C(S)—SR²²,—S—C(O)—N(R²¹)—R²⁸, —S—C(S)—N(R²¹)—R²⁸, —O—C(O)—R²¹, —O—C(S)—R²¹,—O—C(O)—OR²², —O—C(O)—N(R²¹)—R²⁸, —O—C(S)—N(R²¹)—R²⁸, —O—S(O)₂—OR²¹,—O—S(O)—OR²¹, —O—S(O)₂—N(R²¹)—R²⁸, —O—S(O)—N(R²¹)—R²⁸, —O—S(O)₂—R²²,—O—S(O)—R²², —O—P(O)(OR²¹)₂, —O—P(O)(OR²¹)—N(R²¹)—R²⁸,—O—P(O)(N(R²¹)—R²⁸)₂, —N(R²⁹)—C(O)—OR²², —N(R²⁸)—C(O)—SR²²,—N(R²⁸)—C(S)—OR²², —N(R²⁸)—C(S)—SR²², —N(R²⁸)—C(S)—R²¹,—N(R²⁸)—C(O)—N(R²¹)—R²⁸, —N(R²⁸)—C(S)—N(R²¹)—R²⁸, —N(R²⁸)—S(O)₂—R²²,—N(R²⁸)—S(O)—R²², —N(R²⁸)—S(O)₂—OR²¹, —N(R²⁸)—S(O)—OR²¹,—N(R²⁸)—S(O)₂—N(R²¹)—R²⁸, —N(R²⁸)—S(O)—N(R²¹)—R²⁸, —N(R²⁸)—P(O)(OR²¹)₂,—N(R²⁸)—P(O)(OR²¹)—N(R²¹)—R²⁸, —N(R²⁸)—P(O)((R²¹)—R²⁸)₂,—N(R²⁸)—P(O)(R²²)—OR²¹, —N(R²⁸)—P(O)(R²²)—N(R²¹)—R²⁸,—N(R²⁸)—P(O)(R²²)₂, —P(O)(OR²¹)₂, —P(O)(OR²¹)—N(R²¹)—R²⁸,—P(O)(N(R²¹)—R²⁸)₂, —P(O)(R²²)—OR²¹, —P(O)(R²²)—N(R²¹)—R²⁸, —P(O)(R²²)₂,—C(S)—R²¹, —C(S)—SR²¹, —C(S)—N(R²¹)—R²⁸, cyano, halogen, nitro ormethylenedioxy or the radical of an optionally substituted, 5- to14-membered, mono- or polycyclic, saturated or unsaturated heterocyclicring of the formula

in which Q¹ is —C(R²¹)₂—, ═C(R²¹)—, —N(R²⁸)—, —O— or —S—; Q² is —S(O)—or —S(O)₂—; Q³ is —C(R²¹)₂—, ═C(R²¹)—, —N(R²⁸)—, —O—, —S—, —C(R²¹)(—)—or —N(—), where the heterocyclic ring is optionally bonded to the groupA via the free bond in the groups —C(R²¹)(—)— or —N(—)— representing Q³or via any other desired ring carbon atom and where, if the heterocyclicring is bonded to a ring system contained in the group A, theheterocyclic ring can also be fused via two adjacent atoms to the ringsystem in the group A; R² is hydrogen, (C₁-C₈)-alkyl, optionallysubstituted (C₆-C₁₄)-aryl, (C₆-C₁₄)-aryl-(C₁ alkyl optionallysubstituted in the aryl radical or (C₃-C₈)-cycloalkyl; R³ is(C₂-C₈)-alkenylcarbonyl, (C₂-C₈)-alkynylcarbonyl, R⁴CO, COOR⁴,CON(CH₃)R⁴, CONHR⁴, CSNHR⁴; R⁴ is hydrogen or (C₁-C₂₈)-alkyl which canoptionally be mono- or polysubstituted by identical or differentradicals selected from the group consisting of hydroxyl,hydroxycarbonyl, aminocarbonyl, mono- ordi-((C₁-C₁₈)-alkyl)aminocarbonyl, amino-(C₂-C₁₈)-alkylaminocarbonyl,amino-(C₁-C₃)-alkylphenyl-(C₁-C₃)-alkylaminocarbonyl,(C₁-C₁₈)-alkylcarbonylamino-(C₁-C₃)-alkylphenyl-(C₁-C₃)-alkylaminocarbonyl,(C₁-C₁₈)-alkylcarbonylamino-(C₂-C₁₈)-alkylaminocarbonyl,(C₆-C₁₄)-aryl-(C₁-C₈)-alkoxycarbonyl optionally substituted in the arylradical, amino, mercapto, (C₁-C₁₈)-alkoxy, (C₁-C₁₈)-alkoxycarbonyl,Het-CO, optionally substituted (C₃-C₈)-cycloalkyl,HOS(O)₂—(C₁-C₃)-alkyl, R⁹NHS(O)₂—(C₁-C₃)-alkyl,(R⁸O)₂P(O)—(C₁-C₃)-alkyl, tetrazolyl-(C₁-C₃)-alkyl, halogen, nitro,trifluoromethyl or the radical R⁵; R⁵ is optionally substituted(C₆-C₁₄)-aryl, (C₆-C₁₄)-aryl-(C₁-C₈)-alkyl optionally substituted in thearyl radical, a mono- or bicyclic 5- to 12-membered heterocyclic ringwhich can be aromatic, partially hydrogenated or completely hydrogenatedand which can contain one, two or three identical or differentheteroatoms from the group consisting of nitrogen, oxygen and sulfur, aradical R⁶ or a radical R⁶CO—, where the aryl radical and, independentlythereof, the heterocyclic radical can be mono- or polysubstituted byidentical or different radicals from the group consisting of(C₁-C₁₈)-alkyl, (C₁-C₁₈)-alkoxy, halogen, nitro, amino andtrifluoromethyl; R⁶ is R⁷R⁸N, R⁷O or R⁷S or an amino acid side chain, anatural or unnatural amino acid, imino acid, optionallyN—(C₁-C₈)-alkylated or N—((C₆-C₁₄)-aryl-(C₁-C₈)-alkylated) aza-aminoacid or a dipeptide radical wherein the aryl group of the aza-amino acidis optionally substituted and/or in which the peptide bond can bereduced to —NH—CH₂—, esters and amides thereof, wherein hydrogen orhydroxymethyl can optionally stand in place of free functional groupsand/or where free functional groups can be protected by protectivegroups customary in peptide chemistry; R⁷ is hydrogen, (C₁-C₁₈)-alkyl,(C₆-C₁₄)-aryl-(C₁-C₈)-alkyl, (C₁-C₁₈)-alkylcarbonyl,(C₁-C₁₈)-alkoxycarbonyl, (C₆-C₁₄)-arylcarbonyl,(C₆-C₁₄)-aryl-(C₁-C₈)-alkylcarbonyl or(C₆-C₁₄)-aryl-(C₁-C₁₈)-alkyloxycarbonyl, where the alkyl groups areoptionally be substituted by an amino group and/or where the arylradicals can be mono- or polysubstituted by identical or differentradicals from the group consisting of (C₁-C₈)-alkyl, (C₁-C₈)-alkoxy,halogen, nitro, amino and trifluoromethyl, or R⁷ is a natural orunnatural amino acid, imino acid, optionally N—(C₁-C₈)-alkylated orN—((C₆-C₁₄)-aryl-(C₁-C₈)-alkylated) aza-amino acid or a dipeptideradical wherein the aryl group of the aza-amino acid is optionallysubstituted and/or in which the peptide bond can be reduced to —NH—CH₂—;R⁸ is hydrogen, (C₁-C₁₈)-alkyl, optionally substituted (C₆-C₁₄)-aryl or(C₆-C₁₄)-aryl-(C₁-C₈)-alkyl optionally substituted in the aryl radical;R⁹ is hydrogen, aminocarbonyl, (C₁-C₁₈)-alkylaminocarbonyl,(C₃-C₈)-cycloalkylaminocarbonyl, optionally substituted(C₆-C₁₄)-arylaminocarbonyl, (C₁-C₁₈)-alkyl, optionally substituted(C₆-C₁₄)-aryl or (C₃-C₈)-cycloalkyl; R¹⁰ is hydroxyl, (C₁-C₁₈)-alkoxy,(C₆-C₁₄)-aryl-(C₁-C₈)-alkoxy optionally substituted in the aryl radical,optionally substituted (C₆-C₁₄)-aryloxy, amino or mono- ordi-((C₁-C₁₈)-alkyl)amino; R¹³ is hydrogen, (C₁-C₆)-alkyl, optionallysubstituted (C₆-C₁₄)-aryl, (C₆-C₁₄)-aryl-(C₁-C₈)-alkyl optionallysubstituted in the aryl radical, (C₃-C₈)-cycloalkyl or(C₃-C₈)-cycloalkyl-(C₁-C₈)-alkyl; R²¹ is hydrogen, (C₁-C₈)-alkyl,hydroxy-(C₁-C₈)-alkyl, (C₂-C₈)-alkenyl, (C₃-C₁₂)-cycloalkyl,(C₃-C₁₂)-cycloalkyl-(C₁-C₈)-alkyl, optionally substituted (C₆-C₁₄)-aryl,(C₆-C₁₄)-aryl-(C₁-C₈)-alkyl optionally substituted in the aryl radical,optionally substituted heteroaryl or heteroaryl-(C₁-C₈)-alkyl optionallysubstituted in the heteroaryl radical, where alkyl radicals optionallymonosubstituted or polysubstituted by fluorine and the radicals R²¹ canbe identical or different if they occur two or more times; R²² is(C₁-C₈)-alkyl, hydroxy-(C₁-C₈)-alkyl, (C₂-C₈)-alkenyl,(C₃-C₁₂)-cycloalkyl, (C₃-C₁₂)-cycloalkyl-(C₁-C₈)-alkyl, optionallysubstituted (C₆-C₁₄)-aryl, (C₆-C₁₄)-aryl-(C₁-C₈)-alkyl optionallysubstituted in the aryl radical, optionally substituted heteroaryl orheteroaryl-(C₁-C₈)-alkyl optionally substituted in the heteroarylradical, where alkyl radicals can be monosubstituted or polysubstitutedby fluorine and the radicals R²² can be identical or different if theyoccur two or more times; R²⁸ is one of the radicals R²¹—, R²¹N(R²¹)—,R²¹C(O)—, R²²O—C(O)—, R²¹N(R²¹)—C(O)— or R²¹N(R²¹)—C(═N(R²¹))—; R²⁹ isone of the radicals R²²—, R²¹N(R²¹)—, R²¹C(O)—, R²²O—C(O)—,R²¹N(R²¹)—C(O)— or R²¹N(R²¹)—C(═N(R²¹))—; Het is the radical of a 5- to10-membered, monocyclic or polycyclic heterocycle bonded via a nitrogenatom, which can be aromatic or partially unsaturated or saturated andwhich can contain one, two, three or four identical or differentadditional ring heteroatoms from the group consisting of oxygen,nitrogen and sulfur and which can be optionally substituted on carbonatoms and on additional ring nitrogen atoms, where there can beidentical or different radicals R^(h), R^(h)CO or R^(h)O—CO assubstituents on additional ring nitrogen atoms and R^(h) is hydrogen,(C₁-C₈)-alkyl, (C₃-C₈)-cycloalkyl, (C₃-C₈)-cycloalkyl-(C₁-C₈)-alkyl,optionally substituted (C₆-C₁₄)-aryl or (C₆-C₁₄)-aryl-(C₁-C₈)-alkyloptionally substituted in the aryl radical; b, c, and d are 1, e and fare 0; and g and h independently of one another are 0, 1, 2, 3, 4, 5 or6; or a stereoisomeric thereof, or a physiologically tolerable saltthereof.
 2. A compound of the formula I as claimed in claim 1, in whichB is a bivalent radical from the group consisting of (C₁-C₆)-alkylene,(C₂-C₆)-alkenylene, phenylene, phenylene-(C₁-C₃)-alkyl,(C₁-C₃)-alkylenephenyl; R and R⁰ independently of one another arehydrogen, (C₁-C₈)-alkyl, (C₃-C₁₂)-cycloalkyl,(C₃-C₁₂)-cycloalkyl-(C₁-C₈)-alkyl, optionally substituted (C₆-C₁₄)-aryl,(C₆-C₁₄)-aryl-(C₁-C₈)-alkyl optionally substituted in the aryl radical,optionally substituted heteroaryl or heteroaryl-(C₁-C₈)-alkyl optionallysubstituted in the heteroaryl radical, where alkyl radicals can be mono-or polysubstituted by fluorine; R⁴ is hydrogen or (C₁-C₂₈)-alkyl whichcan optionally be mono- or polysubstituted by identical or differentradicals selected from the group consisting of hydroxyl,hydroxycarbonyl, aminocarbonyl, mono- ordi-((C₁-C₁₈)-alkyl)aminocarbonyl, amino-(C₂-C₁₈)-alkylaminocarbonyl,amino-(C₁-C₃)-alkylphenyl-(C₁-C₃)-alkylaminocarbonyl,(C₁-C₁₈)-alkylcarbonylamino-(C₁-C₃)-alkylphenyl-(C₁-C₃)-alkylaminocarbonyl,(C₁-C₁₈)-alkylcarbonylamino-(C₂-C₁₈)-alkylaminocarbonyl,(C₆-C₁₄)-aryl-(C₁-C₈)-alkoxycarbonyl optionally substituted in the arylradical, amino, mercapto, (C₁-C₁₈)-alkoxy, (C₁-C₁₈)-alkoxycarbonyl,optionally substituted (C₃-C₈)-cycloalkyl, HOS(O)₂—(C₁-C₃)-alkyl,R⁹NHS(O)₂—(C₁-C₃)-alkyl, (R⁸O)₂P(O)—(C₁-C₃)-alkyl,tetrazolyl-(C₁-C₃)-alkyl, halogen, nitro, trifluoromethyl or the radicalR⁵; R¹³ is hydrogen, (C₁-C₆)-alkyl, (C₆-C₁₄)-aryl-(C₁-C₈)-alkyloptionally substituted in the aryl radical or (C₃-C₈)-cycloalkyl; or astereoisomer thereof, or a physiologically tolerable salt thereof.
 3. Acompound of the formula I as claimed in claim 1, in which R¹ is one ofthe radicals —S(O)—N(R²¹)—R²⁸, —S(O)₂—N(R²¹)—R²⁸, —O—C(O)—R²¹,—O—C(O)—OR²², —O—C(O)—N(R²¹)—R²⁸, —O—C(S)—N(R²¹)—R²⁸,—O—S(O)₂—N(R²¹)—R²⁸, —O—S(O)—N(R²¹)—R²⁸,—N(R²⁹)—C(O)—OR²²—N(R²⁸)—C(S)—R²¹, —N(R²⁸)—C(O)—N(R²¹)—R²⁸,—N(R²⁸)—C(S)—N(R²¹)—R²⁸, —N(R²⁸)—S(O)₂—R²², —N(R²⁸)—S(O)—R²²,—N(R²⁸)—S(O)₂—OR²¹, —N(R²⁸)—S(O)—OR²¹, —N(R²⁸)—S(O)₂—N(R²¹)—R²⁸,—N(R²⁸)—S(O)—N(R²¹)—R²⁸, —C(S)—R²¹, —C(S)—N(R²¹)—R²⁸ or cyano or theradical of an optionally substituted, 5- to 14-membered, mono- orpolycyclic, saturated or unsaturated heterocyclic ring of the formula

in which Q¹ is —C(R²¹)₂—, ═C(R²¹)—, —N(R²⁸)—, —O— or —S—; Q² is —S(O)—or —S(O)₂—; Q³ is —C(R²¹)₂—, ═C(R²¹)—, —N(R²⁸)—, —O—, —S—, —C(R²¹)(—)—or —N(—)—, where the heterocyclic is optionally bonded to the group Avia the free bond in the groups —C(R²¹)(—)— or —N(—)— representing Q³ orvia any other desired ring carbon atom and where, if the heterocyclicring is bonded to a ring system contained in the group A, theheterocyclic ring can also be fused via two adjacent atoms to the ringsystem in the group A; or a stereoisomer thereof, or a physiologicallytolerable salt thereof.
 4. A compound of the formula I as claimed inclaim 1, in which R⁰ is (C₁-C₈)-alkyl, (C₃-C₁₂)-cycloalkyl,(C₃-C₁₂)-cycloalkyl-(C₁-C₈)-alkyl, optionally substituted (C₆-C₁₄)-aryl,(C₆-C₁₄)-aryl-(C₁-C₈)-alkyl optionally substituted in the aryl radical,optionally substituted heteroaryl or heteroaryl-(C₁-C₈)-alkyl optionallysubstituted in the heteroaryl radical; or a stereoisomeric thereof, or aphysiologically tolerable salt thereof.
 5. A compound of the formula Ias claimed in claim 4, wherein R⁰ is selected from the group consistingof biphenylylmethyl, naphthylmethyl, and benzyl, each of which isunsubstituted or monosubstituted or polysubstituted in the aryl radical;or a stereoisomeric thereof, or a physiologically tolerable saltsthereof.
 6. A compound of the formula I as claimed in claim 1, in whichA is a bivalent radical from the group consisting of methylene,ethylene, trimethylene, tetramethylene, pentamethylene, cyclohexylene,phenylene, phenylenemethyl, methylenephenyl, methylenephenylmethyl; B isa bivalent radical from the group consisting of methylene, ethylene,trimethylene, tetramethylene, vinylene, phenylene, or substitutedmethylene or ethylene; E is R¹⁰CO; R is hydrogen, (C₁-C₆)-alkyl orbenzyl; R⁰ is (C₁-C₈)-alkyl, (C₃-C₈)-cycloalkyl, optionally substituted(C₆-C₁₄)-aryl or (C₆-C₁₄)-aryl-(C₁-C₈)-alkyl optionally substituted inthe aryl radical; R¹ is one of the radicals —S(O)—N(R²¹)—R²⁸,—S(O)₂—N(R²¹)—R²⁸, —O—C(O)—R²¹, —O—C(O)—OR²², —O—C(O)—N(R²¹)—R²⁸,—O—C(S)—N(R²¹)—R²⁸, —O—S(O)₂—N(R²¹)—R²⁸, —O—S(O)—N(R²¹)—R²⁸,—N(R²⁹)—C(O)—OR²², —N(R²⁸)—C(S)—R²¹, —N(R²⁸)—C(O)—N(R²¹)—R²⁸,—N(R²⁸)—C(S)—N(R²¹)—R²⁸, —N(R²⁸)—S(O)₂—R²², —N(R²⁸)—S(O)—R²²,—N(R²⁸)—S(O)₂—OR²¹, —N(R²⁸)—S(O)—OR²¹, —N(R²⁸)—S(O)₂—N(R²¹)—R²⁸,—N(R²⁸)—S(O)—N(R²¹)—R²⁸, —C(S)—R²¹, —C(S)—N(R²¹)—R²⁸ or cyano or theradical of an optionally substituted, 5- to 14-membered, mono- orpolycyclic, saturated or unsaturated heterocyclic ring of the formula

in which Q¹ is —C(R²¹)₂—, ═C(R²¹)—, —N(R²⁸)—, —O— or —S—; Q² is —S(O)—or —S(O)₂—; Q³ is —C(R²¹)₂—, ═C(R²¹)—, —N(R²⁸)—, —O—, —S—, —C(R²¹)(—)—or —N(—)—, where the heterocyclic ring can be bonded to the group A viathe free bond in the groups —C(R²¹)(—)— or —N(—)— representing Q³ or viaany other desired ring carbon atom and where, if the heterocyclic ringis bonded to a ring system contained in the group A, the heterocyclicring can also be fused via two adjacent atoms to the ring system in thegroup A; R² is hydrogen or (C₁-C₈)-alkyl; R³ is R⁴CO, COOR⁴, CONHR⁴, orCSNHR⁴; and g and h independently of one another are the numbers 0, 1, 2or 3; or a stereoisomer thereof, or a physiologically tolerable saltthereof.
 7. A compound of the formula I as claimed in claim 1, in whichR¹³ is (C₁-C₆)-alkyl, (C₆-C₁₄)-aryl-(C₁-C₈)-alkyl optionally substitutedin the aryl radical or (C₃-C₈)-cycloalkyl; or a stereoisomeric thereof,or a physiologically tolerable salts thereof.
 8. The compound of theformula I as claimed in claim 1, wherein R³ is COOR⁴ or CONHR⁴, andwherein —NHR⁴ is the radical of an α-amino acid, anω-amino-(C₂-C₈)-alkylamide thereof, its (C₁-C₈)-alkyl ester, its(C₆-C₁₄)-aryl-(C₁-C₄)-alkyl ester, or its derivative in which thecarboxylic acid group is converted into the group Het-CO, or astereoisomeric thereof, or a physiologically tolerable salt thereof. 9.The compound of the formula I as claimed in claim 8, wherein the radicalof the α-amino acids is selected from the group consisting of valine,lysine, phenylglycine, phenylalanine, tryptophan, (C₁-C₈)-alkyl esters,(C₆-C₄)-aryl-(C₁-C₄)-alkyl esters, and Het-CO derivatives thereof; or astereoisomeric thereof, or a physiologically tolerable salt thereof. 10.A compound of the formula I as claimed in claimed 1, in whichsimultaneously Y is a carbonyl group; Z is N(R⁰); A is ethylene,trimethylene, tetramethylene, pentamethylene, cyclohexylene, phenylene,phenylenemethyl, methylenephenyl or methylenephenylmethyl; B is anunsubstituted or substituted methylene radical; E is R¹⁰CO; R ishydrogen or (C₁-C₄)-alkyl; R⁰ is (C₁-C₈)-alkyl, (C₃-C₈)-cycloalkyl,optionally substituted (C₆-C₁₄)-aryl or (C₆-C₁₄)-aryl-(C₁-C₈)-alkyloptionally substituted in the aryl radical; R¹ is one of the radicals—O—C(O)—R²¹, —O—C(O)—OR²², —O—C(O)—N(R²¹)—R²⁸, —N(R²⁹)—C(O)—OR²²,—N(R²⁸)—C(O)—N(R²¹)—R²⁸, —N(R²⁸)—C(S)—N(R²¹)—R²⁸ or cyano; R² ishydrogen; R³ is the radical CONHR⁴; R⁴ is methyl which is substituted byhydroxycarbonyl and a radical from the group consisting of(C₁-C₄)-alkyl, phenyl and benzyl, or is methyl which is substituted by(C₁-C₈)-alkoxycarbonyl and a radical from the group consisting of(C₁-C₄)-alkyl, phenyl and benzyl, or is methyl which is substituted byHet-CO and a radical from the group consisting of (C₁-C₄)-alkyl, phenyland benzyl; R¹⁰ is hydroxyl or (C₁-C₈)-alkoxy; R¹³ is (C₁-C₆)-alkyl,(C₃-C₇)-cycloalkyl or benzyl; e, f and g are 0; and h is 1 or 2; or astereoisomer thereof, or a physiologically tolerable salt thereof.
 11. Acompound of the formula I as claimed in claim 1, in which a substitutedmethylene radical or substituted ethylene radical representing the groupB carries as a substituent a radical from the group consisting of(C₁-C⁸)-alkyl, (C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl and (C₃-C₈)-cycloalkyl,(C₃-C₈)-cycloalkyl-(C₁-C₄)-alkyl, optionally substituted (C₆-C₁₀)-aryl,(C₆-C₁₀)-aryl-(C₁-C₄)-alkyl optionally substituted in the aryl radical,optionally substituted heteroaryl, andheteroaryl-(C₁-C₄)-alkyloptionally substituted in the heteroaryl radical, or a stereoisomerthereof, or a physiologically tolerable salt thereof.
 12. A compound ofthe formula I as claimed in claim 1, in which B is an unsubstitutedmethylene radical or a methylene radical which is substituted by a(C₁-C₈)-alkyl radical; or a stereoisomer thereof, or a physiologicallytolerable salt thereof.
 13. A compound of the formula I as claimed inclaim 1, in which R¹ is one of the radicals —O—C(O)—R²¹, —O—C(O)—OR²²,—O—C(O)—N(R²¹)—R²⁸, —N(R²⁹)—C(O)—OR²², —N(R²⁸)—C(O)—N(R²¹)—R²⁸,—N(R²⁸)—C(S)—N(R²¹)—R²⁸ or cyano; or a stereoisomer thereof, or aphysiologically tolerable salt thereof.
 14. A preparation comprising oneor more of the compounds of the formula I as claimed in claim 1 or astereoisomer thereof, or a physiologically tolerable salt thereof; andone or more pharmaceutically innocuous carriers and/or additives.
 15. Akit comprising a VLA-4-antagonizing effective amount of one or morecompounds of the formula I as claimed in claim 1 or a stereoisomerthereof, or a physiologically tolerable salt thereof; instructions foruse; and one or more pharmaceutically inocuous carriers and/oradditives.
 16. A method for inhibiting adhesion of leukocytes toendothelial cells in a mammal, comprising administering to a subject inneed thereof a VLA-4 antagonizing amount of a compound according toclaim 1 for a time sufficient to antagonize VLA-4.